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University of Michigan-Ann Arbor
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Identification of regulatory gene networks in the morphologic progression of diabetic nephropathy
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the United States and has a significant impact on human suffering. Mouse models of DN have elucidated important mechanisms contributing to disease progression; however, candidate pathway approaches have yielded limited results. We propose to employ a systems approach to define underlying molecular processes associated with structural damage in DN. The objective of this project is to identify genes and elucidate transcriptional networks that play a role in the development of progressive renal pathology of obesity-induced type 2 diabetes in mice, and then perform cross-species comparison to human transcriptional networks and morphometric analysis of DN. In this proposal, we will employ a rich dataset derived from the intercross of mouse strains resistant (C57BL/6 or B6) or susceptible (BTBR) to diabetes induced by the leptinob mutation. The resulting F2 population (> 500 mice) has been surveyed for many clinical traits and reflects a wide range of susceptibility to diabetic nephropathy. All mice were genotyped for 5,000 single nucleotide polymorphisms (SNPs), 2,000 of which were polymorphic between B6 and BTBR. In addition, gene expression of whole kidney has been surveyed in all F2 mice. We will conduct detailed morphologic examination of formalin-fixed, paraffin-embedded kidneys from all F2 mice, capturing pathologic features as outlined by the DCC such as glomerular mesangial expansion and tubulointerstitial fibrosis. The resulting gene regulatory networks and correlations to clinical and morphologic features will then be compared to renal transcriptional profiling and detailed morphometric analyses previously obtained from a cohort of Southwestern American Indians (n=40) with type 2 diabetes in which protocol kidney biopsies were performed. Our study will yield an unprecedented dataset that will allow us to develop causal regulatory networks that reveal the interaction among genes and intermediate gene expression to the pathophysiology of DN relevant to human disease. Aim 1: Define causal gene regulatory networks of progressive pathologic features of murine DN with a detailed survey of renal morphology in mice that have been genotyped and whole kidney gene expression profiling has been performed. Aim 2: Compare the morphology-derived gene networks obtained from Aim 1 to human kidney transcriptional profiling and morphometric analysis to identify networks relevant to human disease.
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Year: 2017; Items: 2
Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice.
Zhang H, Nair V, Saha J, Atkins KB, Hodgin JB, Saunders TL, Myers MG, Werner T, Kretzler M, Brosius FC
A molecular morphometric approach to diabetic kidney disease can link structure to function and outcome.
Nair V, Komorowsky CV, Weil EJ, Yee B, Hodgin J, Harder JL, Godfrey B, Ju W, Boustany-Kari CM, Schwarz M, Lemley KV, Nelson PJ, Nelson RG, Kretzler M
Year: 2013; Items: 1
Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli.
Hodgin JB, Nair V, Zhang H, Randolph A, Harris RC, Nelson RG, Weil EJ, Cavalcoli JD, Patel JM, Brosius FC, Kretzler M
, 2013 (62), 299 - 308
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The DiaComp Steering Committee is the governing body of the consortium. The principle function of this committee is to guide the scientific direction of the consortium. This is accomplished by creating various subcommittees necessary to advance the scientific goals and providing guidance to the broader complications research community. Policies for the consortium are developed through consultation with the
External Evaluation Committee
The DiaComp Nephropathy Committee has the principal function of furthering the mission of the consortium with regard to diabetic kidney disease.
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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