Diabetic nephropathy is the major cause of end-stage renal disease, but the mediators important in its pathogenesis are incompletely understood and specific therapy remains unavailable. Our laboratory has recently identified an important potential mediator of hyperglycemia: Transforming Growth Factor-beta (TGF-beta), a growth-modulator and pro-sclerotic cytokine. In the proposed studies I hope to identify the mechanisms of regulation of TGF-beta activity and production in mesangial cells by high glucose and to evaluate the significance of its role in mediating diabetic renal disease. Another aim of this proposal is to identify and characterize the cellular signaling pathways utilized by TGF-beta in mesangial cells. The combination of these studies will hopefully provide detailed mechanistic understanding by which TGF-beta interacts with high glucose in renal cells to promote diabetic kidney disease. My academic background and postgraduate training are a strong foundation on which I will rely in preparing myself for a career in research and academic medicine. During my undergraduate and medical school years I was involved in research projects examining different aspects of cell biology and immunology. In the past three years I have been fortunate to work in Dr. Ziyadeh's laboratory to explore many aspects of renal cell biology in relation to diabetic nephropathy. My interaction with many key faculty members at the University of Pennsylvania has also given me a wealth of knowledge and spurred my enthusiasm for the current proposed studies. I eagerly look forward to continue working with Dr. Ziyadeh and to closely collaborate with Dr. Williamson in extending my previous work and breaking ground on new projects. In addition, I have recently joined Thomas Jefferson University and now have the opportunity to learn from Dr. Goldstein and Dr. Khalili. Their expertise will broaden my knowledge to cover intricate aspects of signaling and regulation of promoter elements. An important component of the proposal is the planned training of the candidate in molecular biology and cellular signaling techniques applicable to the study of diabetic kidney disease. This training will be under the tutelage of Dr. Fuad Ziyadeh and Dr. John Williamson from Penn and Dr. Barry Goldstein and Dr. Kamel Khalili at Jefferson. In addition to learning techniques involving cell culture, microinjection, signaling, and promoter regulation, emphasis will be placed on interpretation of results and integration of findings using different approaches. Initially, the candidate will rely heavily on his sponsors and collaborators, and then gradually expand his independent studies during the latter part of the funding period. Thomas Jefferson University offers excellent resources and top-notch investigators in many divisions. It is expected that these activities will establish the candidate as an accomplished independent investigator.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (SRC)
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Rankin, Tracy L
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Thomas Jefferson University
Internal Medicine/Medicine
Schools of Medicine
United States
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Zhu, Yanqing; Casado, Marta; Vaulont, Sophie et al. (2005) Role of upstream stimulatory factors in regulation of renal transforming growth factor-beta1. Diabetes 54:1976-84
Tsuchida, Ken-ichi; Zhu, Yanqing; Siva, Senthuran et al. (2003) Role of Smad4 on TGF-beta-induced extracellular matrix stimulation in mesangial cells. Kidney Int 63:2000-9
Sharma, K; Mc Gowan, T A; Wang, L et al. (2000) Inhibition of type I and III IP(3)Rs by TGF-beta is associated with impaired calcium release in mesangial cells. Am J Physiol Renal Physiol 278:F1022-9
McGowan, T A; Sharma, K (2000) Regulation of inositol 1,4,5-trisphosphate receptors by transforming growth factor-beta: implications for vascular dysfunction in diabetes. Kidney Int Suppl 77:S99-103
Sharma, K; Wang, L; Zhu, Y et al. (1999) Renal type I inositol 1,4,5-trisphosphate receptor is reduced in streptozotocin-induced diabetic rats and mice. Am J Physiol 276:F54-61
Sharma, K; Eltayeb, B O; McGowan, T A et al. (1999) Captopril-induced reduction of serum levels of transforming growth factor-beta1 correlates with long-term renoprotection in insulin-dependent diabetic patients. Am J Kidney Dis 34:818-23
Sharma, K; Considine, R V (1998) The Ob protein (leptin) and the kidney. Kidney Int 53:1483-7
Wang, L; Zhu, Y; Sharma, K (1998) Transforming growth factor-beta1 stimulates protein kinase A in mesangial cells. J Biol Chem 273:8522-7
Cohen, M P; Sharma, K; Guo, J et al. (1998) The renal TGF-beta system in the db/db mouse model of diabetic nephropathy. Exp Nephrol 6:226-33
Sharma, K; Wang, L; Zhu, Y et al. (1997) Transforming growth factor-beta1 inhibits type I inositol 1,4,5-trisphosphate receptor expression and enhances its phosphorylation in mesangial cells. J Biol Chem 272:14617-23

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