Leslie Bruggeman, Ph.D.
Associate Professor
Department of Medicine, MetroHealth Medical Center
Center for AIDS Research
Case Western Reserve University
TEL: (216) 778-7603
FAX: (216) 778-4321


Curriculum Vitae

Research Interest(s)
Molecular and cellular biology of chronic kidney diseases. Areas of special interest include: pathogenesis of HIV-associated nephropathy; transcriptional regulation of HIV-1 and eukaryotic gene expression; podocyte cell biology; transcriptional regulation during epithelial cell differentiation and in kidney development. In vitro modeling of the glomerular filtration barrier.

Selected Publications
Bruggeman, L. A., S. Martinka, and J. S. Simske. Expression of TM4SF10, a claudin/EMP/PMP22 family cell junction protein, during mouse kidney development and podocyte differentiation. Dev. Dyn. 236:596-605 (2007).

Ross, M. D., S. Martinka, A. Mukherjee, J. R. Sedor, C. Vinson, and L. A. Bruggeman. Math6 expression in kidney development and altered expression in a mouse model of glomerulosclerosis. Dev. Dyn. 235:3102-3109 (2006).

Martinka, S. and L. A. Bruggeman. Persistent NF-kB activation in renal epithelial cells in a transgenic mouse model of HIV-associated nephropathy. Am. J. Physiol. Renal Physiol. 290: F657-665 (2006).

Ross, M. J., S. Martinka, V. D. D’Agati, and L. A. Bruggeman. NF-kB regulates Fas-mediated apoptosis in HIV-associated nephropathy. J. Am. Soc. Nephrol. 16: 2403-2411 (2005).

Gharavi A. G., T. Ahmad, R. Wong, R. Hooshyar, J. Vaughn, S. Oller, R. Z. Frankel, L. A. Bruggeman, V. D. D`Agati, P. E. Klotman, and R. P. Lifton. Mapping a locus for susceptibility to HIV-1-associated nephropathy to mouse chromosome 3. Proc. Natl. Acad. Sci. 101:2488-2493 (2004).

Kevin D. Bunting, Ph.D.
Associate Professor of Medicine
Department of Medicine, Division of Hematology/Oncology
Case Western Reserve University
TEL: (216) 368-5694
FAX: (216) 368-1166


Research Interest(s)
My main area of research continued in the field of hematopoietic stem cell biology. Since these cells are potential targets for treating a wide variety of blood diseases, understanding the basic mechanisms regulating their proliferation, differentiation, self-renewal, mobilization, and migration is extremely important. These processes determine the efficacy of a stem cell transplant and they are directly relevant for possible clinical application in cell and gene therapy. We take a genetics approach to the study of signal transduction pathways and modulation of extracellular matrix interactions of stem cells. These studies heavily use transgenic and knockout mouse models for various genes of interest. This work is also directly relevant for the Case Cancer Center and the Center for Stem Cell and Regenerative Medicine, both of which I am actively involved.

There are two major areas of research that are funded by NIH R01 grants.
1. R01DK059380 - JAK/STAT Signaling in Hematopoietic Stem Cells – the purpose of this work is to define the role of two specific signal transducer and activator of transcription (STAT) family members in hematopoiesis. We are focused on STAT3 and STAT5 because these two factors are regulated by early acting hematopoietic cytokines. The STAT5 project is most well developed (Bunting et al., Blood, 2002; Bradley et al. Blood 2002; Bradley et al. Blood 2004). We have demonstrated a severe competitive repopulating defect in mice in which full-length STAT5a and STAT5b have been deleted. Current studies have focused on a remaining endogenous N-terminal truncated STAT5 alternative reading frame that is expressed at very low levels in these mice. In certain cell types, such as mast cells, we find that the truncated form is selected for and can confer unique cytokine responsiveness to stem cell factor (SCF). Ongoing studies will address the role of STAT5 in SCF responses and possible implications in adhesion, migration, or homing of stem cells. We have also obtained and are currently characterizing true null mice in collaboration with Lothar Hennighausen at the NIH.

2. R01HL073738 - Role of TIMPs in Hematopoietic Stem Cell Biology – the purpose of this work is to define the role of the tissue inhibitor of matrix metalloproteinase (TIMP)/matrix metalloproteinase (MMP) balance in controlling hematopoietic stem cell engraftment. We have developed retroviral vector systems for overexpression of TIMP-1, TIMP-2, and MMP-9 in wild-type and TIMP-1-/- mice. These studies will determine whether TIMPs have MMP-independent growth factor activity in regulating early hematopoiesis. Also, these studies will determine the effects of transgenic MMP-9 on the early engraftment and mobilization of hematopoietic stem and progenitor cells. MMP-9 release following cytokine or chemokine induced mobilization is believed to play a role in release of stem cells from the bone marrow niche, however, MMP-9 transgenic mice have never been reported. Further studies will address the physiological role of TIMP-1 as a negative regulator of MMP-9 under conditions of hematopoietic stress.

Selected Publications
Bradley, H.L., Hawley, T.S., Bunting, K.D. Cell intrinsic defects in cytokine responsiveness of STAT5-deficient hemapoietic stem cells. Blood, (100); 3983-89, 2002.

Bradley, H.L., Couldrey, C., Bunting, K.D. Hematopoietic-repopulating defects from STAT5-deficient bone marrow are not fully accounted for by loss of thrombopoietin responsiveness. Blood, 103; 2965-72, 2004.

Haviernik, P. Lahoda, C., Bradley, H.L., Hawley, T.S., Ramezani, A., Hawley, R.G., Stetler-Stevenson, M., Stetler-Stevenson, W.G., Bunting, K.D. Tissue inhibitor of matrix metalloproteinase-1 overexpression in M1 myeloblasts impairs IL-6-induced differentiation. Oncogene (23); 9212-19, 2004.

Randall D. Cebul, M.D.
Professor of Medicine, Epidemiology and Biostatistics
Director, Center for Health Care Research & Policy
TEL: (216) 778-3902
FAX: (216) 778-3945

Biosketch
Curriculum Vitae

Research Interest(s)
Dr. Cebul studies and applies methods in epidemiology and the decision sciences to examine and improve health care delivery. Areas of special emphasis include clinical policy-relevant research and decision support for preventive services and chronic illnesses. Current studies focus on diabetes and cerebrovascular disease.

Selected Publications
Votruba ME, Cebul RD. Redirecting patients to improve stroke outcomes: implications of a volume-based approach in one urban market. Med Care. 2006; 44 (12): 1129-1136

Murray PK, Dawson NV, Thomas CL, Cebul RD. Are we selecting the right patients for stroke rehabilitation in nursing homes? Arch Phys Med Rehabil. 2005;86(5):876-880.

Murray PK, Love TE, Dawson NV, Thomas CL, Cebul RD. Rehabilitation services following the implementation of the nursing home prospective payment system: differences related to patient and nursing home characteristics. Medical Care 2005 Nov;43(11):1109-15.

Katzan IL, Cebul RD, Baker DW, et.al. The effect of pneumonia on mortality among patients hospitalized for acute stroke. Neurology. 2003; 60:620-625.

Baker DW, Einstadter D, Thomas CL, Husak SS, Gordon NH, Cebul RD. Mortality trends during a program that publicly reported hospital performance. Med Care. 2002; 40: 879-890.

Michael W. Cho, Ph.D.
Assistant Professor of Medicine
Department of Medicine,
Division of Infectious Diseases
Director, Molecular Virology and Gene Expression Core
Center for AIDS Research
Case Western Reserve University
TEL: (216) 844-7767
FAX: (216) 844-1409

Web Page

Research Interest(s)
Molecular virology and viral immunology of several important human pathogens, namely human immunodeficiency virus (HIV-1), smallpox, SARS coronavirus and West Nile virus. The primary activity of the lab is to develop and/or improve vaccines against HIV-1, smallpox and SARS-CoV. The laboratory uses molecular biology techniques to generate novel vaccine candidates and evaluate their immunogenicity in laboratory animals. The laboratory is also involved in characterizing structural-functional properties of viral proteins that allow viruses to enter cells as well as assessing host immune responses that are mounted against those proteins.

Selected Publications
Han, D. P., H. G. Kim, Y. B. Kim, L. L. M. Poon, M. W. Cho (2004). Development of a safe neutralization assay for SARS-CoV and Characterization of S glycoprotein. Virology. 326: 140-149.

Kim, Y. B., D. P. Han, C. Cao, M.W. Cho (2003). Immunogenicity and ability of variable loop-deleted human immunodeficiency virus type 1 envelope glycoproteins to elicit neutralizing antibodies. Virology 305: 124-137

Cho, M. W. (2003). Subunit protein vaccines: Theoretical and practical considerations for HIV-1. Curr. Mol. Med. 3:243-263. (Review).

Alfred F. Connors, Jr., M.D.
Chair, Department of Medicine
Case Western Reserve University at
MetroHealth Medicial Center
Charles H. Rammelkamp Jr. Professor of Medicine
Case Western Reserve University School of Medicine
TEL: (216) 778-8266
FAX: (216) 778-5823

Biosketch
Curriculum Vitae

Research Interest(s)
Evaluation & measurement of patient outcomes, determining effectiveness of therapy, devices & processes of care, medical decision making, management of the seriously ill, and cost-effectiveness analysis.

Selected Publications
Stukenborg GJ, Wagner DP, Connors AF Jr. A comparison of two comorbidity measures with and without information from prior hospitalizations. Medical Care, 2001;39;727-739. Go to Publication

Arseneau KO, Cohn SM, Comminelli F, Connors AF Jr. Cost-utility of initial medical management for Crohn’s disease perianal fistulae. Gastroenterology 2001;120:1640-1656. Go to Publication

Rose JH. O`Toole EE. Dawson NV. Thomas C. Connors AF Jr. Wenger N. Phillips RS. Hamel MB. Reding DT. Cohen HJ. Lynn J. Generalists and oncologists show similar care practices and outcomes for hospitalized late-stage cancer patients. Medical Care. 2000;38:1103-1118. Go to Publication

Johnston KC, Connors AF Jr, Wagner DP, Haley EC Jr. Risk adjustment effect in stroke clinical trials. Stroke. 2004;35:43-45 Go to Publication

Stukenborg GJ, Wagner DP, Harrell FE, Oliver MN, Kilbridge K, Lyman J, Einbinder J, Connors AF. Hospital discharge abstract data on comorbidity improved the prediction of death among patients hospitalized with aspiration pneumonia. J Clin Epidemiol 2004; 57: 522-532. Go to Publication

Pamela B. Davis, M.D., Ph.D.
Professor of Pediatrics, Physiology & Biophysics,
and Molecular Biology & Microbiology
Department of Medicine,
Veterans Administration Medical Center
Arline H. and Curtis F. Garvin, M.D., Research Professor
Senior Associate Dean for Research
Case Western Reserve University
TEL: (216) 368-4370
FAX: (216) 368-4223

Web Page
Curriculum Vitae

Research Interest(s)
The goal of our laboratory is to understand the pathophysiology of cystic fibrosis (CF), a common fatal genetic disease, and to ultimately to ameliorate or cure it. CF is caused by defects in a gene that encodes a chloride channel, CFTR, but the patients succumb to pulmonary infection and inflammation. One line of work in our lab investigates how dysfunction of CFTR leads to infection and particularly the excess inflammatory response that characterizes the CF lung disease. In cell and animal models, CF cells and CF mice have excessive cytokine responses to bacterial stimulation, which contributes to lung damage. We study the mechanism of this excessive response and how to prevent it without impairing host defenses. We have shown previously that high dose ibuprofen ameliorates the excessive inflammation, and it is our current working hypothesis that the mechanism of this effect is by binding to PPAR *, a nuclear receptor which can interact with the pro inflammatory transcription factor NF *B, in reciprocal fashion. Ultimately, we will build upon our findings in cell and animal models for design of a clinical trial.

A second line of work is to devise means of delivering the corrective CFTR gene to the airways of patients with CF. We have constructed DNA nanoparticles that consist of plasmid DNA compacted with polylysine and stabilized with polyethylene glycol, in which the smallest diameter is less than that of the nuclear pore. This small size allows nuclear access in nondividing cells. These nanoparticles can transfect airway epithelium in vivo in CF mice to a sufficient extent to correct not only the CF chloride transport defect but also some of its downstream consequences. In addition, these nanoparticles seem to be quite nontoxic, and they can be dosed repeatedly without decrement in effect. A single dose Phase I clinical trial in the nose of human patients with CF was completed, with the result that 8 of 12 subjects had improvement in chloride transport, with no adverse effects attributable to the drug. Current work is investigating potential improvements in the DNA nanoparticles (including targeting and improvement of the plasmid construct), aerosolization of the particles for pulmonary treatment, and extension of the molecular targets to delivery of siRNA directed against respiratory viruses.

Selected Publications
Ziady, AG, Gedeon, CR. Miller, T, Quan, W. Payne JM, Hyatt SL, Fink TL, Muhammed O, Oette S, Kowalczyk,T. Pasumarthy M, Moen, RC, Cooper MC, and Davis, P.B. Transfection of Airway Epithelium by Stable PEGylated Poly L lysine DNA Nanoparticles In Vivo, Mol Ther. 8(6):936 47, 2003.

Ziady AG, Gideon CR, Muhammad O, Stillwell V, Oette SM, Fink TL, Quan W, Kowalczyk TH, Hyatt SL, Peischl A, Seng JE, Moen RC, Cooper MJ, and Davis PB. Minimal Toxicity of Stabilized compacted DNA nanoparticles in the murine lung. Mol Ther. 8(6):948 56, 2003.

van Heeckeren AM Schluchter, MD Davis, PB Role of Cftr Genotype in the Response to Chronic Pseudomonas aeruginosa Lung Infection in Mice Am J. Physiology:Lung Cell and Molecular Physiology 2004 ;287(5):L944 52.

Neal V. Dawson, M.D.
Professor of Medicine, Epidemiology and Biostatistics
MetroHealth Medical Center Staff Since 1982
Center for Health Care Research and Policy
TEL: (216) 778-3901
FAX: (216) 778-3945


Biosketch
Curriculum Vitae

Research Interest(s)
Dr. Dawson is a specialist in general internal medicine and works in the MetroHealth Primary Care Internal Medicine Clinic (Firms). He has published on the use of Firms for research, especially in health services. He recently completed a Firm trial on alcohol screening and management in a primary care setting. He is currently looking at predictors of alcohol use among nonaddicted Hepatitis C patients. In addition he has considerable experience in the conduct of large studies and in multvariable analyses of large databases.

Selected Publications
Murray PK, Love TE, Dawson NV, Thomas CL, Cebul RD. Rehabilitation services following the implementation of the nursing home prospective payment system: Differences related to patient and nursing home characteristics. Medical Care 2005; 43:1109 15.

Bailit JL, Love TE, Dawson NV. Quality of obstetric care and risk-adjusted primary cesarean rates. Am J Ob Gyn 2006;194:402-7.

Bailit JL, Schulkin J, Dawson NV. Risk-adjusted cesarean rates: What risk factors for cesarean delivery are important to practicing obstetricians? Am J Reprod Med 2006; (in press).

Lindstrom HA, Smyth KA, Sami SA, Dawson NV, Patterson MB, Bohinc JH, Post SG, Barber MJ, Ollerton S, Singer M, Whitehouse PJ. Medication use to treat memory loss in dementia: perspectives of people with dementia and their caregivers. Dementia 2006;5(1):27-50.

Stoller EP, Hund AJ, Webster NJ, Blixen CE, Perzynski AT, McCormick RA, Kanuch SW, Dawson NV. Alcohol consumption within the context of hepatitis C: a qualitative study of non-problematic drinkers. Alcohol and Alcoholism 2006; 41(5):546-552.

Dorr G. Dearborn, Ph.D., M.D.
Professor of Pediatrics
Mary Ann Swetland Professor of
Environmental Health Sciences
Case Western Reserve University




Research Interest(s)
Primary Research Interest-
Extensive Mold Exposure: Health Effects for Infants and Children
Acute Pulmonary Hemorrhage in Infants:
Over the past ten years, there have been 38 infants with acute pulmonary hemorrhage cared for at our pediatric hospital; five infants have died. The initial case-control study of the first 10 infants, led by the CDC, found an association with exposure to moldy home environments. Additional experience supports the association since 88% of the total 38 infants have come from water-damaged home environments containing Stachybotrys chartarum and other fungi. Removing these infants from their original home environments resulted in a 17-fold decrease in re-bleeding (Dearborn, et al., Pediatrics, 110:627,2002). The association is further supported by infant animal studies. Additional factors of environmental tobacco smoke and bacterial endotoxin are being considered.

Related Research Projects-
1. Continued collection and analysis of acute respiratory tract samples from infants presenting with acute pulmonary hemorrhage.
2. Further development of quantitative PCR and immunological biomarkers to document acute fungal exposure in infants and children.
3. Extension of our acute fungal exposure model in infant rats to a more chronic, low level exposure.
4. Kinetics of mycotoxin and proteinase release from fungal spores.

Mold-related Health Effects in Children:
A. Children of families who have left their homes because of adverse health effects apparently due to extensive mold contamination have been seen for clinical and psychometric evaluation. Initial, uncontrolled observations note that most laboratory tests including IgG fungal serologies are seldom abnormal. Symptom profiles obtained by retrospective questionnaire reflect significant reductions of most general health and respiratory symptoms after the children are out of the moldy environments. Children exposed prior to six years of age appear to have an increased incidence of language deficits.

Related Research Projects-
1. Case-control study of infants and siblings of mold exposure and possible neurotoxicity as seen by Visual Contrast Sensitivity and language psychometric evaluation.

B. Children living in damp, moldy home environments are at-risk of developing respiratory illness, both acutely and longer term. In a recently completed study supported by US HUD and US EPA (Cuyahoga County Urban Mold and Moisture Project, UMMP), explored the relationship between mold, moisture, asthma triggers and the respiratory health of children living in inner city neighborhoods throughout Greater Cleveland. Clinical and environmental assessments before and after targeted remediation found significant improvement in moderately severe asthmatic children compared to randomized controls whose homes were not remediated (decrease in symptom score (Am Acad Ped Asthma Health Survey) p<0.006 and symptom days p<0.003). The home intervention group also had a lower rate of exacerbations requiring hospitalization or an emergency room visit compared to control asthmatics (1/29 vs. 11/33, respectively, p=.003). Environmental assessments found a significant decrease in the visual mold (p=0.0035) and the ratio of indoor/outdoor mold species (p=0.049) in remediated versus control homes. The large data base generated by the extensive semi-quantitative culturing of fungi and the quantitative PCR measurements of 33 fungal species continues to be analyzed. While the significance of the UMMP study is limited due to the small number of families and homes investigated, the observed clinical improvements are very encouraging and underline the need to expand on these observations in larger studies in cooperation with other pulmonary centers.

Selected Publications
Dearborn, DG, Smith, PG, Dahms, BB, Allan, TM, Sorenson, WG, Montana, E, Etzel, RA, Clinical profile of thirty infants with acute pulmonary hemorrhage in Cleveland. Pediatrics, 110:627-637, 2002.

Yike, I, and Dearborn, D.G. Pulmonary effects of Stachybotrys chartarum in animal studies. In: Advances in Applied Microbiology, Sick Building Syndrome, D. Strauss (ed), Elsevier Inc, 2004, p.241-273.

Vesper, SJ, Varma, M, Wymer, LJ, Dearborn, DG, Sobolewski, J, Haugland, RA. Quantitative polymerase chain reaction analysis of fungi in dust from homes of infants who developed idiopathic pulmonary hemorrhaging, J Occup Environ Med, 46:596-601, 2004

Clark W. Distelhorst, M.D.
Professor of Medicine
Professor of Pharmacology
Charles S. Britton II Professor of Hematology/Oncology
Case Western Reserve University
TEL: (216) 368-4546
FAX: (216) 368-8919


Research Interest(s)
Research in the laboratory of Dr. Clark Distelhorst has two fundamental goals. One is to understand how glucocorticosteroid hormones (dexamethasone, prednisone) induce apoptosis in lymphocytes and the other is to understand how Bcl-2 inhibits apoptosis, emphasizing the role of Bcl-2 on the endoplasmic reticulum. Because glucocorticosteroid hormones induce apoptosis in young lymphocytes, glucocorticoid hormones have an important role in the treatment of a wide variety of lymphoid cancers. Understanding the mechanism of apoptosis induction by glucocorticoids will enable us to develop novel therapies and overcome resistance to glucocorticoid-induced apoptosis, while providing novel insight into a fundamentally important mechanism of apoptosis induction. Conversely, the primary action of Bcl-2 is to inhibit apoptosis. In this way Bcl-2 promotes cancer cell survival and inhibits cell killing by chemotherapeutic agents. The laboratory has many accomplishments. Using oligonucleotide microarrays, we have profiled the gene changes induced by dexamethasone in lymphoma cell lines and in primary murine thymocytes. This profile has uncovered many interesting genes and has set the stage for a number of projects in our lab. For example, we have recently discovered that the proapoptotic BH3-only protein Bim is induced by dexamethasone in normal primary thymocytes and in lymphoma cells. Thus, Bim is a glucocorticoid-induced “death gene”. As revealed by our microarray findings, a number of other interesting genes are induced by dexamethasone that may contribute to the life-death decision of cells treated with dexamethasone. On another front, our laboratory was the first, over ten years ago, to indicate that Bcl-2 works at the level of the endoplasmic reticulum to regulate calcium signals involved in mediating apoptosis.

Determining the effect of Bcl-2 on calcium signals is one of the highest priorities in our laboratory today. In addition, we are interested in the role of ER-localized Bcl-2 in regulating protein-protein interactions with other family members. Recently we have employed targeting sequences to direct Bcl-2 to either ER or mitochondria. Paradoxically we discovered that Bcl-2 targeted to the outer mitochondrial membrane induces apoptosis, whereas Bcl-2 targeted selectively to the ER is antiapoptotic.

Selected Publications
Thomenius MJ, Wang NS, Reineks EZ, Wang Z, and Distelhorst CW. Bcl-2 on the endoplasmic reticulum regulates Bax activity by binding to BH3 only proteins. J. Biol. Chem. 278:6243-6250, 2003

Wang Z, Malone MH, He H, McColl KS, Distelhorst CW. Microarray analysis uncovers the induction of the pro-apoptotic BH3-only protein Bim in multiple models of glucocorticoid induced apoptosis. J. Biol. Chem. 278:23861-23867, 2003

Wang Z, Malone MH, Thomenius MJ, Zhong F, Xu F, Distelhorst CW. Dexamethasone-induced gene 2 (dig2) is a novel prosurvival stress gene induced rapidly by diverse apoptotic signals. J Biol Chem 278:27053-27058, 2003

Chen R, Valencia I, Zhong F, McColl KS, Roderick HL, Bootman MD, Berridge MJ, Conway SJ, Holmes AB, Mignery GA, Velez P, Distelhorst CW. Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate. J Cell Biol 166:193-203, 2004

Malone M, Wang Z, Distelhorst CW. The glucocorticoid-induced gene tdag8 encodes a pro-apoptotic G protein-coupled receptor whose activation promotes glucocorticoid-induced apoptosis. J Biol Chem 279:52850-52859, 2004

Kenneth J. Gustafson, Ph.D.
Staff Scientist, Dept. of Orthopaedics
MetroHealth Medical Center
Department of Biomedical Engineering
Neural Engineering Center
Case Western Reserve University
TEL: (216) 778-3801



Research Interest(s)
Research interests focus on understanding the systems-level neurophysiology and neural control of pelvic functions, and using this information to design and develop neural prostheses that interface with native spinal neural circuitry and restore physiologic function. Bladder dysfunction can have a devastating clinical impact. Therefore my efforts include developmental and pre-clinical studies to translate research advances into clinical implementation at the earliest opportunity. Current projects in both animal models and individuals with neural dysfunction include peripheral activation of spinal circuits to activate and inhibit bladder function, development of an implanted neural prosthesis able to selectively record and stimulate neural pathways and restore bladder function (a bladder pacemaker), neural recording of organ activity as a control source for closed-loop neural prostheses, commercial activities to translate research discoveries into clinical practice, combining myoplasty and neuromuscular stimulation to harness skeletal muscle power for cardiac assist and rehabilitation applications, and exploring neural anatomy to improve peripheral nerve electrode design.

Selected Publications
Gustafson KJ, Creasey GH and Grill WM. A urethral afferent mediated excitatory bladder reflex exists in humans. Neuroscience Letters, 360(1-2): 9-12, 2004.

Gustafson KJ, Creasey GH and Grill WM. A Catheter Based Method to Activate Urethral Sensory Nerve Fibers. Journal of Urology, 170(1):126-129, 2003.

Gustafson, KJ, JD Sweeney, J Gibney, LA Fiebig-Mathine. Skeletal muscle ventricle pressure-volume properties conform to dynamic and static conditioning. Annals of Thoracic Surgery. 76(3):828-835, 2003.

Sylvie Hauguel-de Mouzon, Ph.D.
Professor of Reproductive Biology
Director, Molecular Biology Laboratory
OBGYN
Schwartz Center for Metabolism and Nutriton
TEL: (216) 778-3148, (216) 778 4262
FAX: (216) 778-1574


Research Interest(s)
The primary research interest of our group is in the mechanisms that regulate the growth of the fetus in utero in normal and pathological pregnancies. Over the last 10 years, our group has investigated the interactions between the maternal compartment and the feto-placental unit and addressed the molecular mechanisms that regulate maternal-fetal exchanges. Additionally, the regulatory mechanisms related to pathological pregnancies associated with diabetes, which often results in excessive fetal growth (macrosomia) have been studied. A strong emphasis has been put on the role of leptin during pregnancy. Earlier studies have shown that the placental controls fetal growth by producing hormones that modify fetal nutrition and fat accretion. Leptin is one of these hormones synthesized in high amounts by the placenta as well as by maternal and fetal adipose tissue.

OUR group has been instrumental in showing that the placenta synthesizes as much leptin as white adipose tissue and is a primary site for leptin action. We have characterized the main molecular pathways of placental leptin signaling. We have established that fetal plasma leptin is a marker of fat accretion in the human fetus. We have shown that diabetes modifies placental transcriptome in a way that favors fetal overgrowth and obesity, inducing chronic inflammation and increasing placental lipid strorage. This research is currently being extended into mechanisms of placental and fetal programming.

Current research projects focus on 4 main areas.
1. The origin of pregnancy-induced insulin resistance through longitudinal transcriptome/proteome studies of white adipose tissue and skeletal muscle analyzed at different stages of pregnancy.
2. Transcriptional regulation of placental leptin using in vitro models of trophoblast cells.
3. Mechanisms of leptin signaling in control of gene expression using microarray analysis
4. Regulation of fetal fat accretion in relation to placental structure and function. Resolution of these issues should help establish the yet missing link between modifications of maternal environment and the development of fetal obesity. These studies have important clinical implications as they relate to our understanding of the fetal origin of adult metabolic diseases (glucose intolerance, diabetes and obesity) and ultimately its prevention.

Selected Publications
Lepercq J, Guerre-Millo M, Vidal H, Cauzac M, Timsit J, Hauguel-de Mouzon S. 2001 Prenatal leptin production: Evidence that fetal adipose tissue produces leptin. J. Clin. Endocrinol. Metab. 86, 2409-2413

Boileau P, Cauzac C, Pereira MA, Girard J and Hauguel-de Mouzon S 2001. Dissociation between insulin-mediated signaling pathways and biological effects in placental cells : role of PKB and MAPKinase phosphorylation. Endocrinology 142, 3974-3979.

Kirwan JP, Hauguel-de Mouzon S, Lepercq J, Challier JC, Huston-Presley L, Friedman JE, Kalhan SC, and Catalano PM. 2002. TNF-alpha is a primary mediator of insulin resistance in human pregnancy. Diabetes 51, 2207-2213.

Grosfeld A, André J, Hauguel-de Mouzon, Berra E, J. Pouyssegur J. Guerre-Millo M. Hypoxia-inducible factor 1 HIF-1 transactivates the human leptin gene promoter 2002. J. Biol. Chem 277, 42953-42957.

Cauzac,M, D. Czuba , Girard J and S. Hauguel-de Mouzon (2003) Transduction of leptin growth signals in placental cells is independent of JAK-STAT activation Placenta 24, 378-384.

Radaelli, T., Varastehpour, A, Catalano P and S Hauguel-de Mouzon (2003). Gestational Diabetes induces placental genes for chronic stress and inflammatory pathways Diabetes 52 : 2951-2958.

Christina S. Hirsch, M.D., Ph.D.
Assistant Professor of Medicine
Division of Infectious Diseases
Case Western Reserve University
TEL: (216) 368-0441



Research Interest(s)
Primary: T-cell apoptosis and its mediators and mechanisms; with a focus on the contribution of both T-cell and macrophage apoptosis on host immune reactivity in HIV-infected and –uninfected persons with M. tuberculosis infection/disease.Secondary: Study of the immune response during human tuberculosis; particularly cytokine responses to M. tuberculosis and its components, and the role of blood monocytes in depressed anti-tuberculous defense mechanisms.

Selected Publications
Hirsch CS, Toossi Z, Vanham G, Johnson JL, Peters P, Okwera A, Mugerwa R, Mugeyenyi P, and Ellner JJ. Apoptosis and T-cell hyporesponsiveness in pulmonary tuberculosis. J Inf Dis 179:945-53. 1999.

Hirsch CS, Toossi Z, Johnson JL, Luzze H, Ntambi E, Peters P, McHugh M, Okwera A, Joloba M, Mugeyenyi P, Mugerwa RD, Terebuh P, and Ellner JJ. Augmentation of apoptosis and IFN-production at sites of active MTB infection in human tuberculosis. J Inf Dis, 183:779-88, 2001.

Ribeiro-Rodrigues R, Resende Co T, Ribeiro F, Palaci M, Johnson JL, Sá RT, Maciel EL, Pereira Lima FL, Dettoni V, Toossi Z, Boom WH, Dietze R, Ellner JJ, and Hirsch CS. Sputum cytokine levels in patients with pulmonary tuberculosis as markers of response to treatment. Clin Diag Lab Immunol, 9:818-23, 2002

Satish C. Kalhan, M.D.
Professor, Department of Pediatrics
Director, Robert Schwartz, M.D. Center for Metabolism & Nutrition
MetroHealth Medical Center
Case Western Reserve University
TEL: (216) 778-8643




Research Interest(s)
The metabolic adaptive responses of the mother during normal pregnancy, which contribute to normal fetal growth and the transition of the normal fetus to extrauterine life, is the major focus of our group. Innovative stable isotopic tracers and gas chromatography-mass spectrometry methods are utilized in combination with indirect respiratory calorimetry in order to quantify metabolism in vivo. Perturbations in metabolism, e.g. as a consequence of maternal diabetes or intrauterine growth retardation, are being examined. Recent studies from our group have shown that, in human pregnancy, changes in maternal glucose and fat metabolism occur in parallel with the increasing fetal demands, while nitrogen conservation appears to occur early in gestation in anticipation of the fetal needs. Other studies, in collaboration, are examining the role of maternal insulin resistance on maternal protein metabolism and fetal growth, the significance and mechanism of insulin resistance in puberty, and the consequence of insulin resistance on muscle protein metabolism in liver disease. The ultimate goal of these studies is to develop effective intervention strategies for optimal clinical and nutritional management of these physiological and pathophysiological states.

The mechanism of reduced environmental oxygen and hypoxemia on intrauterine growth restriction is being examined in the rat model of pregnancy. The alterations in transport of nutrients, e.g. glucose and amino acids, from the mother to the fetus are quantified using in vivo and in vitro methods.

Selected Publications
Kalhan SC, Parimi P, Van Beek R, Gilfillan C, Saker F, Gruca L, Sauer PJJ: Estimation of gluconeogenesis in newborn infants. Am J Physiol 281:E991-E997, 2001.

Kalhan SC, Mahajan S, Burkett E, Reshef L, Hanson RW: Glyceroneogenesis and the source of glycerol for hepatic triacylglycerol synthesis in humans. J Biol Chem 276: 12928-12931, 2001.

Kalhan S, Rossi K, Gruca L: Decompensation of leucine nitrogen turnover in gestational diabetes. Diabetes Care 23:1033-4, 2000.

Kalhan S, Peter-Wohl S: Hypoglycemia: What is it for the neonate? Am J Perinatol 17:11-18, 2000.

Kalhan S: Protein metabolism in human pregnancy. Am J Clin Nutr 71:1249S-1255S, 2000.

Perry Kannan, Ph.D.
Staff Scientist (Associate Professor)
TEL: (216) 778-1156
FAX: (216) 778-7554


Research Interest(s)
My laboratory is focused on delineating the molecular events of oncogenesis, especially the pivotal roles played by transcription factors. We have taken transcription factor AP-2 as a model system. Deregulation of AP-2 has been implicated in many carcinogenic events including Ras-oncogenic signal transduction pathway, breast cancer, adenocarcinoa and melanoma. We are particularly interested in two of these carcinogenic events. One is the oncogenicity induced by the HER-2 proto-oncogene which is overexpressed in about one fourth of human breast cancers. AP-2 transcription factors bind to the HER-2 gene promoter and activate its expression. In a striking concurrence, anomalous abundance of AP-2alpha protein or its homolog AP-2gamma is also detected with HER-2 in mammary tumor-derived cell lines. This indicates that deregulation of AP-2 is the preceding pathogenic event and probably the pivotal one in this type of mammary carcinogenesis. My laboratory examined the process of AP-2 gene expression in mammary carcinoma cell lines to pinpoint where the aberration had occurred. We excluded a number of possibilities such as increased gene copy number, gene transcription, and mRNA stability. We find that AP-2 proteins have extended stability in breast cancer cell lines. Further investigation reveals that the breast cancer cells are defective in the ubiquitin-dependent proteasomal-degradation pathway which results in the accumulation of AP-2 proteins. Our studies confirm that this defect is the prime reason that eventually causes overexpression of HER-2 gene and culminates in breast cancer. In this ongoing research, we are tracking the disease further backwards to identify the nature of the aberration in the proteasomal-degradation pathway, studying the prevalence in breast cancer patients and developing prognostic markers and strategies for pharmacological intervention. The second one is the ras-oncogene signal transduction pathway in teratocarcinoma. Intriguingly, AP-2 causes sequestration of coactivators when it is aberrantly overexpressed in ras-transformed cells. Our investigation reveals that many accessory proteins are necessary for the normal functioning of transcription factor AP-2 which it shares with other activators. The balance of cellular transcriptional activity is affected when the levels of AP-2 proteins are anomalously high. We identified two coactivators: positive coactivator-4 and poly(ADP-ribose) polymerase-1. Our studies show that both have tumor suppressor property.

Selected Publications
Li, M., Naidu, P., Yu, Y., Berger, N. A., and Kannan, P. 2004. Dual regulation of AP-2a transcriptional activation by poly(ADP-Ribose) polymerase-1. Biochem. J. 382:323-329 Go to Publication

Li, M., Wang, Y., Yu, Y., Li, M., Nishizawa, M., Nakajima, T., Ito, S., and Kannan, P. 2002. The human transcription factor AP 2gamma: gene structure, promoter, and expression in mammary carcinoma cell lines. Gene 302:43-51 Go to Publication

Wankhade S, Yu Y, Weinberg J, Tainsky MA, Kannan P. 2000. Characterization of the activation domains of AP-2 family transcription factors. J Biol Chem. 275:29701-29708. Go to Publication

Kannan P, Yu Y, Wankhade S, Tainsky MA. 1999. PolyADP-ribose polymerase is a coactivator for AP-2-mediated transcriptional activation. Nucleic Acids Res. 27:866-874. Go to Publication

Kannan P, Tainsky MA. 1999. Coactivator PC4 mediates AP-2 transcriptional activity and suppresses ras-induced transformation dependent on AP-2 transcriptional interference. Mol Cell Biol. 19:899-908. Go to Publication

Diana Kunze, Ph.D.
Professor of Neurosciences
Senior Staff Scientist Rammelkamp
TEL: (216) 778-8967
FAX: (216) 778-2090

Curriculum Vitae
Web Page

Research Interest(s)
Mechanisms of cardio-respiratory control. Areas of interest include (a) contributions of ion channels to the plasticity of blood pressure and heart rate control (b) role of ion channels in adaptions to intermittent hypoxia as a model for sleep apnea. Techniques include patch clamp electrophysiological analysis of cultured neurons and brain slice preparations, immunohistochemistry, calcium imaging, neuronal modeling, molecular biology including single cell RT-PCR and analysis of knockout mice with ion channel defects.

Selected Publications
Doan T.N.; Kunze, D.L. Contribution of the hyperpolarization-activated current (IH) to the resting membrane potential of neonatal rat nodose sensory neurons, J. Physiol. 514:125-138 1999

Balkowiec, A,. Kunze, D.L.; Katz, D Brain-derived neurotrophic factor acutely inhibits AMPA-mediated currents in developing sensory relay neurons. J Neurosci. 20:1904-11. 2000

Andrews, E. M., Kunze,D.L. Voltage-gated potassium channels in chemoreceptor sensory neurons of rat petrosal ganglion Br Research, 897:199-203 2001

Kenneth Laurita, Ph.D.
Assistant Professor of Medicine and Biomedical Engineering
Senior Scientist
TEL: (216) 778-7340
FAX: (216) 778-1261

Curriculum Vitae

Research Interest(s)
Cellular mechanisms of cardiac arrhythmias using fluorescent imaging of transmembrane potential and intracellular calcium in the intact heart. Cardiac repolarization and its influence on arrhythmia vulnerability. Intracellular calcium homeostasis and its role in arrhythmogenesis. Mechanisms of cardiac impulse propagation and block. Instrumentation and software design for imaging the electrical activity of the heart.

Selected Publications
Laurita KR, Singal A. Mapping action potentials and calcium transients simultaneously from the intact heart. American Journal of Physiology. 2001;280:H2053-H2060.

Laurita KR, Rosenbaum DS. The interdependence of modulated dispersion and tissue structure in the mechanism of unidirectional block. Circulation Research. 2000;87:922-928.

Laurita KR, Girouard SD, Akar FG, Rosenbaum, DS. Modulated dispersion explains changes in arrhythmia vulnerability during premature stimulation of the heart. Circulation. 1998;98:2774-2780.

Michael M. Lederman, M.D.
Scott R. Inkley Professor of Medicine
Professor of Biomedical Ethics, Pathology, Microbiology and Molecular Biology
Director, Center for AIDS Research
Case Western Reserve University
TEL: (216) 844-8786
FAX: (216) 844-5523


Research Interest(s)
Identifying mechanisms of immune deficiency and host defenses in HIV disease, and in exploring methods to enhance them.

Selected Publications
Sieg, S.F., Bazdar, D.A., Lederman, M.D. Impaired T cell receptor-mediated induction of Ki67 by naïve CD4+ T cells is only occasionally corrected by exogenous interleukin-2 in HIV-1 infection. J. Immunology 171:5208-14, 2003.

Salkowitz, J.R., Sieg, S.F., Harding, C.V., Lederman, M.M. In vitro human memory CD8 T cell expansion in response to cytomegalovirus requires CD4+ T cell help. J. Inf. Dis. 204:971-83, 2004.

Martin, M.P., Lederman, M.M., Hutcheson, H., Nelson, G.W., Goedert, J.J., Detels, R., Buchbinder, S., Hoots, K., Vlahov, D., Obrien, D.J., Carrington, M., Association of DC-SIGN promoter polymorphisms with increased risk for parenteral but not mucosal acquisition of HIV-1 infection. J. Virol. 78:14053-56, 2004.

Lederman, M.M., Veazey, R., Hartley, O., Mosier, D., Dufour, J., Mefford, M., Piatak, M., Jr., Salkowitz, J.R., Rodriguez, B., Blauvelt, A., Offord, R. Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science 306:485-7, 2004.

Sanford Markowitz, M.D., Ph.D.
Markowitz-Ingalls Professor of Cancer Genetics
Investigator, Howard Hughes Medical Institute
Howard Hughes Medical Institute Laboratories
Case Western Reserve University
TEL: (216) 368-1976
FAX: (216) 368-8928


Research Interest(s)
My laboratory studies the genetics of human colon cancer. Among our achievements was the discovery that TGF-beta receptors are colon cancer tumor suppressor genes that are mutated in human colon cancers, the discovery that methylation of the hMLH1 repair gene promoter is the pathogenetic event that induces sporadic colon cancers that have microsatellite instability, and the finding that methylation of the E-Cadherin gene is the obligate "second hit" leading to gastric cancers in families with the hereditary diffuse gastric cancer syndrome. Recent discoveries include finding evidence for a novel familial colon cancer gene on chromosome 9q, and discovering a "celebrex like" anti-cancer activit of the TGF-beta pathway. Current research interests in the laboratory include finding the actual new familial colon cancer gene on chromsome 9q, developing new molecular diagnostic tests for early detection of colon cancer, and elucidating genes that play a role in metastatic colon cancers.

Selected Publications
Recent citations from the laboratory are:Yan M, Rerko R, Platzer P, Dawson D, Willis J, Tong M, et al. 15-Hydroxyprostaglandin Dehydrogenase, a COX-2 oncogene antagonist, is a TGF-ß induced suppressor of human gastrointestinal cancers. Proc Natl Acad Sci U S A 2004;101:17468-17473. (selected for a cover citation)

Wiesner G, Daley D, Lewis S, Ticknor C, Platzer P, Lutterbaugh J, et al. A subset of familial colorectal neoplasia kindreds linked to chromosome 9q22.2-31.2. Proc Natl Acad Sci U S A 2003;100:12961-12965.

Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP, Lakshmi Kasturi L, et al. SLC5A8: A novel sodium transporter, is a tumor suppressor gene silenced by methylation in human colonic aberrant crypt foci and colon cancers. Proc Natl Acad Sci U S A 2003;100:8412-17.

E. Regis McFadden Jr., M.D.
Argyl J. Beams Professor of Medicine
MetroHealth Medical Center
Professor
Case Western Reserve University
TEL: (216) 778-4848




Research Interest(s)
Pulmonary Medicine / Asthma Airway Diseases

R. Tyler Miller, M.D.
Professor of Medicine and Physiology
Department of Physiology and Biophysics
Case Western Reserve University
TEL: (216) 791-3800 x5180
FAX: (216) 231-3470

Biosketch

Research Interest(s)
My laboratory studies two areas, G protein signaling and responses of epithelial cells to mechanical force. In the area of G protein signaling, we focus on the calcium-sensing receptor (CaR), a receptor that is expressed in the parathyroid where it controls PTH secretion, in the kidney where it contributes to regulation of Na, K, Cl, Ca, Mg, and H2O balance, and in many other epithelial tissues where its function is not well defined. Our current studies are designed to define the molecular mechanisms that determine the signaling specificity for this receptor by identifying interacting and scaffolding proteins. We are currently working with the inwardly-rectifying K channel family, Kir4.x along with the lipid signaling pathways that regulate it, and filamin, a cytoskeletal protein that also acts as a scaffold. These two proteins appear to be responsible for some of the unique biologic effects of the CaR. The Kir4.x channels may be responsible for the profound effects of the CaR on fluid and electrolyte balance. We are preparing to study the role of this receptor in regulating salt and water balance in humans in a GCRC setting. Filamin appears to be responsible for CaR trafficking and the organization of additional proteins in its neighborhood. These issues are being addressed in cultured cell and genetic systems. We are also studying the effects of mechanical force on glomerular podocytes, cells that are exposed increased mechanical force due to increased glomerular pressure and flow following renal injury. In this work, we are evaluating the responses of cells to growth on substrates with a range of mechanical properties reflecting exposure of the cells to different levels of tension. We are measuring cell structure (cytoskeleton focusing on filamin, the most important protein for determination of cytoskeletal strength and rigidity) growth, migration, and metabolic function including production of second messengers and oxygen radicals. This work is designed to address the reasons why glomerular injury is a progressive process.

Selected Publications
Awata H, Huang C, Handlogten M.E., Miller R.T. Interaction of the Calcium-sensing Receptor and Filamin, a Potential Scaffolding Protein. J Biol Chem 276 (37): 34871-9, 2001.

Huang C, Handlogten ME, Miller RT. Parallel Activation of Phosphatidylinositol 4-Kinase and Phospholipase C by the Extracellular Calcium-sensing Receptor. J Biol Chem. 277 (23):20293-300, 2002.

Huang C, Hujer K, Zhenzhen W, Miller RT. Am J Physiol cell Physiol 286: C22-C30, 2004.

David S. Rosenbaum, M.D.
Director, Heart & Vascular Research Center
Chief, Division of Cardiology
Professor of Medicine, Biomedical Engineering, Physiology & Biophysics
TEL: (216) 778-2005
FAX: (216) 778-4924

Curriculum Vitae
Heart & Vascular Research Web Page

Research Interest(s)
Mechanisms of cardiac arrhythmias. Areas of special interest include; application of novel imaging technologies (e.g. voltage-sensitive dyes) to investigations of electrical heterogeneities in the heart, cardiac repolarization, electrophysiological characterization of genetically engineered mice, electrophysiology of failing and remodeled myocardium, computer modeling of electrical properties in the heart, mechanisms of electrical alternans and arrhythmogenesis, and prediction and prevention of sudden cardiac death.

Selected Publications
Wan X, Laurita KR, Pruvot E, Rosenbaum DS. Molecular correlates of repolarization alternans in cardiac myocytes. J. Molecular Cellular Cardiology 2005;39:419-428

Eloff BC, Gilat E, Wan X, Rosenbaum DS. Pharmacological modification of cardiac gap junctions to enhance cardiac conduction: Evidence supporting a novel target for antiarrhythmic therapy. Circulation 2003;108:3157-3163

Pastore JM, Rosenbaum DS: Role of structural barriers in the mechanism of alternans-induced reentry. Circulation Research 2000;87:1157-1163.

Poelzing S, Rosenbaum DS. Altered connexin43 expression produces arrhythmia substrate in heart failure. Am J Physiol 2004;287:H1762-70

Rosenbaum DS, Jackson LE, Smith JM, Garan H, Ruskin JN, Cohen RJ: Electrical alternans and vulnerability to ventricular arrhythmias. N Engl J Med 1994;330:235-241.

Jeffrey Schelling, M.D.
Associate Professor of Medicine
Case Western Reserve University
Director, Division of Nephrology and Hypertension
MetroHealth Medical Center
TEL: (216) 778-4993, (216) 778-4159
FAX: (216) 778-8248, (216) 778-4321


Curriculum Vitae
Laboratory Web Page

Research Interest(s)
The primary interest of my lab is investigation of cellular and molecular mechanisms regulating chronic renal diseases. Much of the laboratory effort is devoted toward understanding the pathogenesis of tubular atrophy, which predicts chronic kidney disease progression. Approaches to these studies focus on apoptosis and cell survival pathways. We have determined that activation of the renal tubular epithelial cell NHE1 Na+/H+ exchanger promotes cell survival, in part by functioning as a scaffold for assembly of signaling complexes. Additional interests of the lab include interrogation of αvß8 integrin function in mesangial cells. Using in vitro and animal model systems, we are investigating the possibility that αvß8 directs small molecular weight G-protein pathways, which may regulate mesangial cell differentiation and/or glomerular capillary function. Finally, we are engaged in collaborative projects, which employ high throughput screening methods to identify diabetic nephropathy susceptibility genes.

Selected Publications
Schelling JR, Abboud HE, Nicholas SB, Pahl MV, Sedor JR, et al, on behalf of the Family Investigation of Nephropathy and Diabetes Research Group. Genome-wide scans for estimated GFR in multi-ethnic diabetic populations: The Family Investigation of Diabetes and Nephropathy. Diabetes 57:235-243, 2008. Go to Publication

Lakhe-Reddy S, Khan S, Konieczkowski M, Jarad G, Wu KL, Reichardt LF, Takai Y, Bruggeman LA, Wang B, Sedor JR, Schelling JR. ß8 integrin binds RhoGDI-1 and activates Rac1 to inhibit mesangial cell myofibroblast differentiation. J Biol Chem 281:19688-19699, 2006. Go to Publication

Wu KL, Khan S, Lakhe-Reddy S, Jarad G, Obejero-Paz CA, Mukherjee A, Konieczkowski M, Sedor JR, Schelling JR. The NHE1 Na+/H+ exchanger recruits ERM proteins to regulate Akt-dependent cell survival. J Biol Chem 279:26280-26286, 2004. Go to Publication

Wu KL, Khan S, Lakhe-Reddy S, Wang L, Jarad G, Miller RT, Konieczkowski M, Brown AM, Sedor JR, Schelling JR. Renal tubular epithelial cell apoptosis is associated with caspase cleavage of the NHE1 Na+/H+ exchanger. Am J Physiol 284: F829-F839, 2003. Go to Publication

Jarad G, Wang B, Miao H, Khan S, Wu K, DeVore J, Nishimura SL, Wible BA, Konieczkowski M, Sedor JR, Schelling JR. Fas activation induces renal tubular epithelial cell ß8 integrin expression and function in the absence of apoptosis. J Biol Chem 277:47826-47833, 2002. Go to Publication

William P. Schilling, Ph.D.
Associate Professor
Physiology and Biophysics, CWRU
Bioscientific Staff
TEL: (216) 778-8965
FAX: (216) 778-8997

Curriculum Vitae

Research Interest(s)
Calcium signaling in vascular endothelial cells and the role of ion channels in cell death.

Selected Publications
Estacion, M., Sinkins, W.G., and Schilling, W.P. Regulation of Drosophila TrpL channels by phospholipase C-dependent mechanisms. J. Physiol. (Lond.) 2001, 530.1: 1-19.

Estacion, M. and Schilling, W.P. Maitotoxin-induced cell death and membrane blebbing in vascular endothelial cells. BMC:Physiology, 2001, 1:2.

Goel, M., Garcia, R. Estacion, M. and Schilling, W.P. Regulation of Drosophila TRPL channels by immunophilin dFKBP59. J. Biol. Chem. 2001, In Press.

John Sedor, M.D.
Professor of Medicine and Physiology & Biophysics,
School of Medicine, Case Western Reserve University
Vice President of Research,
Department of Medicine,
MetroHealth Medical Center
TEL: (216) 778-4993
FAX: (216) 778-4978


Biosketch
Laboratory Web Page
Research Highlights

Research Interest(s)
We focus on progressive kidney disease mechanisms. The overall goal of the lab is to define the clinical, cellular and genetic bases of kidney disease in order to identify new therapies and diagnostic tests. Current projects include identification of nephropathy susceptibility genes and defining mechanisms of kidney disease progression using in vitro (cell culture) and animal models. Using gene discovery assays, the lab has discovered a protein that appears to critically regulate kidney filtration function (WTIP) and is now characterizing this novel protein’s function and looking for mutations in its DNA sequence in families with multiple cases of kidney disease.Keywords: protein-protein interaction, proteomics, genomics, cell-cell adhesion, podocyte, cytoskeletonTechniques used: Cell Culture, Molecular biology, LC/MS, Protein Chemistry, Phage Display Immunohistochemistry, Protein Expression, DNA library construction, PCR differential display, SAGE, expression profiling, 2-hybrid system, genetic-epidemiological statistical approaches.

Selected Publications
Srichai, M.B., M. Konieczkowski, S. Barathan, P. S. Hayden, S. Khan, P. Mundel, S.B. Lee, L.A. Bruggeman, J.R. Schelling, and J.R. Sedor. A WT1 co-regulator controls podocyte phenotype by shuttling between adhesion structures and nucleus. J. Biol. Chem. 279: 14398-408, 2004. Go to Publication

Liu, J., L. Zhang, D. Wang, H. Shen, M. Jiang, P. Mei, P.S. Hayden, J.R. Sedor and H. Hu. Congenital diaphragmatic hernia, kidney agenesis and cardiac defects associated with Slit3-deficiency in mice. Mech. Dev. 120:1059-70 2003. Go to Publication

Knowler, W.C., J. Coresh, R.C. Elston, B.I. Freedman, S.K. Iyengar, P.L. Kimmel, J. Olson, R. Plaetke, J.R. Sedor, and M.F. Seldin on behalf of the Family Investigation of Nephropathy and Diabetes Research Group. The family investigation of diabetes and nephropathy (FIND). Design and Methods. J. Diabetes Complications, in press, 2004.

Hayden, P.S., M.A. El-Meanawy, J.R. Schelling, and J.R. Sedor. DNA expression analysis: SAGE (Serial Analysis of Gene Expression), microarrays and kidney disease. Curr. Opin. Nephrol. Hypertens. 12: 407-414, 2003. Go to Publication

Iyengar, S.K., K.A. Fox, M. Schachere, F. Manzoor, M.E. Slaughter, A.M. Covic, S.M. Orloff, P.S. Hayden, J.M. Olson, J.R. Schelling, and J.R. Sedor. Linkage analysis of candidate loci for end stage renal disease due to diabetic nephropathy. J. Amer. Soc. Neph. 14: S195-S201, 2003. Go to Publication

Ashwini R. Sehgal, M.D.
Director, The Center for Reducing Health Disparities
Associate Professor of Medicine, Biomedical Ethics, and Epidemiology and Biostatistics
Physician, Division of Nephrology
TEL: (216) 778-7728
FAX: (216) 778-8401

Biosketch
Curriculum Vitae

Research Interest(s)
Identifying and overcoming barriers to quality of care, Complex health interventions, Adequacy of hemodialysis, Nutrition in renal failure, Access to kidney transplantation, Medical activism.

Selected Publications
Sehgal AR, Leon JB, Siminoff LA, Singer ME, Bunosky LM, Cebul RD. Improving the quality of hemodialysis treatment: A community-based randomized controlled trial to overcome patient-specific barriers. Journal of the American Medical Association. 2002;287:1961-1967.

Goyal M, Mehta RL, Schneiderman LJ, Sehgal AR. Economic and health consequences of selling a kidney in India. Journal of the American Medical Association. 2002;288:1589-1593.

Sehgal AR. Do quality improvement efforts reduce race and gender disparities in health outcomes? Journal of the American Medical Association. 2003;289:996-1000.

Richard F. Silver, M.D.
Associate Professor of Medicine
Associate Professor of Infectious Diseases
Case Western Reserve University




Research Interest(s)
Dr. Silver is interested in protective human immunity to Mycobacterium tuberculosis and in development of assays for assessment of the virulence M. tuberculosis in human model systems. Current studies focus on the ability of lymphocytes to limit intracellular growth of virulent M. tuberculosis within blood monocytes and alveolar macrophages. Studies have assessed the capacity of CD4+ and CD8+ T-cells, and of natural killer cells (NK cells) to mediate killing of intracellular M. tuberculosis . Correlation has been made between the capacities of these lymphocyte subsets inhibit intracellular M. tuberculosis and their ability to produce activating cytokines, and to mediate lytic and apoptotic killing of M. tuberculosis-infected mononuclear phagocytes. Dr. Silver’s laboratory is also investigating the ability of M. tuberculosis-specific immune responses to be mobilized to the lungs of PPD-positive subjects using a novel bronchoscopic antigen-challenge protocol. Dr. Silver’s laboratory has demonstrated that PPD challenge results in recruitment of antigen specific Th1-like CD4+ T-cells to the lungs of individuals with immunity to M. tuberculosis. This approach has also demonstrated the importance of resident memory cells in initiating chemokine responses to M. tuberculosis within the lung. Local antigen challenge may be useful in evaluating and optimizing new strategies for vaccination against tuberculosis. More generally, these studies offer a means to characterize the mechanisms involved in development of Th1-like responses in the human lung. In addition, Dr. Silver has utilized a model of low-level infection of human monocytes and alveolar macrophages to assess the virulence of M. tuberculosis. In this system, the capacity for intracellular growth of M. tuberculosis isolates appears to correlate with molecular epidemiologic assessments of strain virulence. Current studies involve both assessment of the alterations in intracellular growth seen in recombinant organisms in which specific candidate virulence genes have been disrupted, and comparison of the growth of clinical isolates of M. tuberculosis obtained from well-characterized households in Uganda.

Selected Publications
Q Li, CC Whalen, R Larkin, L Zukowski, J Albert, MD Cave, and RF Silver. “Differences in rate and variability of intracellular growth of a panel of clinical isolates of Mycobacterium tuberculosis within a human monocyte model ”, Infection and Immunity, 2002, 70: 6489-6493.

F Hoft, S Worku, B Kampmann, C Whalen, JJ Ellner, CS Hirsch, RB Brown, R Larkin, Q Li, H Yun, and RF Silver. “Investigation of the relationships between immune-mediated inhibition of mycobacterial growth and other potential surrogate markers of protective TB immunity”, J. Inf. Diseases, 2002, 186: 1448-1457.

RF Silver, Q Li, L Zukowski, S Kotake, F Pozuelo,A Krywiak, and R Larkin“Recruitment of antigen-specific Th1 responses to the human lung following segmental antigen challenge with Purified Protein Derivative of M. tuberculosis”, Am. J. Resp. Cell. and Mol. Biol., 2003, 29: 117-123.

J Walrath,, L Zukowski, A Krywiak, and RF Silver. “Th1-like resident effector-memory cells and the initiation of pulmonary recall responses to Mycobacterium tuberculosis” (submitted).

Kingman P. Strohl, M.D.
Professor of Anatomy
Professor of Oncology
Professor of Medicine
Case Western Reserve University
TEL: (216) 231-3399
FAX: (216) 231-3475


Research Interest(s)
Obstructive sleep apnea is the most common disorder of respiratory control, present in some 2-5% of the population and producing neurocognitive and cardiovascular morbidity. This state-dependent condition has a clear genetic component, with a substantially increased risk for snoring and sleep apnea among relatives of affected individuals. Almost a third of the variance in the severity of sleep apnea in a US population is explained by familial clustering. The pathways by which inheritance could predispose to sleep apnea include anatomic features of the obese condition and of craniofacial form; however, current data suggest that these heritable traits explain only a half of familial cases. Our research focuses on those factors related to respiratory control, namely the control of ventilation and the impact of sleep on ventilatory drive. We are interested in how the elements of ventilatory act and interact to produce repetitive events during sleep, which in turn influence the pathogenesis of illness. Our pre-clinical models suggest genetic risk influences features of dynamic control including the response to changes in chemosensory drive and the response to re-oxygenation, including the appearance of unstable breathing. Thus research has begun to identify a biologic map for causative factors that modulate the physiology of sleep apnea, and provide insight into pathways that could increase (or decrease) the risk of disease progression or that might be pharmacologically influenced to reduce apnea expression.

Selected Publications
Iyengar SK, Stein CM, Russo K, Erokwu BO, Strohl KP. The fa Leptin Receptor Mutation and the Heritability of Respiratory Frequency in a Brown Norway and Zucker Intercross. J Appl Physiol 97(3):811-20, 2004 Epub 2004 Mar 19

Gonsenhauser I, Han F, Wilson CG, Strohl KP, Dick TE. Strain Differences in Murine Ventilatory Behavior Persists after Anesthesia. J Appl Physiol 97(3):888-894, 2004

Friedman L, Haines A, Klann K, Gallaugher L, Salibra L, Han F, Strohl KP. Sleep and Ventilatory Behavior among A/J and C57BL/6J Mouse Strains. J Appl Physiol 97(5):1787-95, 2004.

Mehra R, Strohl KP. Incidence of Serious Adverse Events during Nocturnal Polysomnography. Sleep 27: 1379-83, 2004

Papp KK, Strohl KP. The Effects of an Intervention to Teach Medical Students about Obstructive Sleep Apnea. Sleep Medicine (in press)

Dennis M. Super, M.D., M.P.H.
Associate Professor, Department of Pediatrics
Case Western Reserve University
Associate Chairman, Pediatric Research
MetroHealth Medical Center
TEL: (216) 778-1213




Research Interest(s)
As both a pediatrician and an epidemiologist, my research interests range from diagnostic test development to the growth and development of children. For example, our past work in the field of gestational diabetes mellitus has shown that one can accurately diagnose gestational diabetes in the first trimester of pregnancy in a high-risk population. In addition, we have shown that non-obese women with gestational diabetes have a lower risk of gestational diabetes in subsequent pregnancies than their obese counterparts. We are currently in the process of developing normative data for the 50 gram glucose tolerance tests in each trimester of pregnancy.

I am also the co-principal investigator of a study funded by NIDA to evaluate the effect of intrauterine exposure to cocaine on the neonate’s cardiovascular system. As part of this study, we are also evaluating the association of cocaine exposure to intrauterine growth retardation by studying the infant’s body composition, placenta morphology, and various fetal growth hormones.

In addition to the above studies, I also serve as both research methodologist and biostatistician to the General Clinical Research Center as well as the Robert Schwartz, M.D., Center for Metabolism and Nutrition. In this capacity, I assist our investigators in the design and analysis of their studies.

Selected Publications
Raghavan CV, Super DM, Chatburn RL, Savin SM, Fanaroff AA, Kalhan SC: Estimation of total body water in very low birthweight (VLBW) infants using bioelectric impedance and [18O] labeled water. Am J Clin Nutr 68:668-674, 1998.

Super DM, Edelberg SC, Philipson EH, Hertz RH, Kalhan SC: Diagnosis of gestational diabetes in early pregnancy. Diabetes Care 14:288-294, 1991.

Philipson EH, Super DM: Gestational diabetes mellitus: Does it recur in subsequent pregnancies? Am J Obstet Gynecol 160:1324-1331, 1989.

Zahra Toossi, M.D.
Professor of Medicine
Division of Infectious Diseases
Case Western Reserve University
TEL: (216) 368-4844



Research Interest(s)
Primary: Study of the basis for the dysregulation of the immune response during human tuberculosis with specific focus on cytokine responses to M. tuberculosis and its components, and mononuclear phagocytic effector mechanisms.

Secondary: Study of the impact of tuberculosis on HIV disease with specific focus on mechanisms by which activation of mononuclear cells during tuberculosis and by M. tuberculosis and its products enhance expression of HIV by latently – or newly infected cells.

Selected Publications
Ribeiro-Rodrigues R, Resende Co T, Johnson JL, Ribeiro F, Palaci M, Sa RT, Maciel EL, Pereira Lima FE, Dettoni V, Toossi Z, Boom WH, Dietze R, Ellner JJ, Hirsch CS. Sputum cytokine levels in patients with pulmonary tuberculosis as early markers of mycobacterial clearance. Clin diagn Lab Immunol. 9:818-23; 2002.

Collins KR, Qionones-Mateu ME, Wu M, Luzze H, Johnson JL, Hirsch CS, Toossi Z, Arts EJ. Human immunodeficiency virus type 1 (HIV-1) quasispecies at the sites of Mycobacterium tuberculosis infection contribute to systemic HIV-1 heterogeneity. J virol. 76:1697-706, 2002.

Aung H, Sherman J, Tary-Lehman M, Toossi Z. Anaylsis of transforming growth factor-beta 1 (TGF-beta1) expression in human monocytes infected with Mycobacterium avium at a single cell level by ELISPOT assay. J Immunol Methods. 1;259:25-32, 2002.

Bingcheng Wang, Ph.D.
Associate Professor
Department of Medicine, MetroHealth Medical Center
Department of Pharmacology and the Ireland Cancer Center
Case Western Reserve University
TEL: (216) 778-4256
FAX: (216) 778-4321


Laboratory Web Page

Research Interest(s)
A primary interest of my laboratory is the molecular mechanism governing development and malignant progression of prostate cancer. Currently we are focusing on the role of Eph receptor tyrosine kinases and their ephrin ligands. Eph kinases constitute 25% of the 60 or so receptor tyrosine kinases in human genome. However, their role in tumor development and progression are only beginning to be investigated. We have found that EphA2 kinase is highly expressed in osseous metastasis of human prostate cancer. In vitro, ligand activation of EphA2 inhibits prostate cancer proliferation and migration, suggesting that it may function as a novel tumor suppressor gene. Indeed, our studies using EphA2 knockout model show disruption of EphA2 predispose them to tumor development.

We are exploiting the intrinsic tumor suppressive function of EphA2 in prostate cancer intervention using multidisciplinary strategies including:
1) Characterize novel signal pathways initiated by EphA kinases to identify new points of therapeutic intervention.
2) Investigate the structural bases of EphA2 ectodomain interaction with its cognitive ligands for structure-based drug discovery.
3) Further characterize and optimize peptide and small compound agonists of EphA2 kinase that we have already identified.
4) Develop and perform preclinical assays to evaluate the therapeutic efficacy of EphA2 agonists in athymic mouse xenograft and genetically engineered mouse model systems. A long-term goal is to realize eventual clinical applications of EphA2 agonists in the treatment and prevention of human prostate cancer.

Another interest of my lab is the role of Eph kinases in renal development and physiological function. Several in vitro and in vivo model systems are in use to evaluate how deletion of EphA2 and other Eph kinases may affect branching morphogenesis of renal epithelial cell cultures in vitro and embryonic kidney development in utero. Finally, in the adult kidney, EphA2 is highly expressed in inner medulla and papilla, the most hypertonic site due to urinary concentration. We are currently investigating how EphA2 may contribute to the hypertonic response, which could have important physiological and clinical implications.

Selected Publications
Miao, H., Wei, B.-R., Peehl, D. M., Li, Q., Burnett, E., Alexandrou, T., Sedor, J. R., Schelling, J. R., and Wang, B. (2001). EphA kinase activation inhibits Ras/MAPK pathway. Nature Cell Biology 3:527-530

Miao, H., Nickel, C., Cantley, L. G., Leslie A. Bruggman, 1Laura N. Bennardo and Wang, B. (2003). EphA Kinase Activation Regulates HGF-Induced Epithelial Branching Morphogenesis. Journal of Cell Biology 162:1681-1692.

Miao, H., Guan, J.-L., Shen, T. L., Strebhardt, K., Paquale, E. B., and Wang, B. Inhibition of integrin-mediated cell adhesion and spreading, but not migration requires the catalytic activity of EphB3 kinase. (Published online Nov. 2004). Journal of Biological Chemistry. 280:923-932.