The primary goal of this proposal is to explore the hypothesis that the Notch pathway plays an important role in the development of diabetic nephropathy. We found via large scale genome screening that Notch pathway proteins are regulated in animal models of diabetic nephropathy. In vitro studies showed that the hyperglycemic milieu activates the Notch pathway and this activation leads to the dysfunction of glomerular cells. These observations suggest that the Notch pathway plays an important role in mediating diabetic complications.
The specific aims of the proposal are to:
Aim one is to characterize the molecular mechanism of glucose induced Notch pathway activation in podocytes. In the second specific aims we will determine the role of Notch pathway activation in glucose induced podocyte dysfunction. We will achieve this aim via genetic manipulation of Notch signaling. Under the third specific aim we will determine the in vivo functional role of glomerular epithelial Notch in mediating the development of diabetic nephropathy via the use of genetically engineered animals. In the long-term, this work will elucidate molecular signaling mechanisms determining specific, context dependent cellular responses, such as apoptosis and growth arrest that may be triggered by hyperglycemia in different cell types.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK076077-04
Application #
7774330
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2007-03-01
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$330,159
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Beckerman, Pazit; Bi-Karchin, Jing; Park, Ae Seo Deok et al. (2017) Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice. Nat Med 23:429-438
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Ko, Yi-An; Yi, Huiguang; Qiu, Chengxiang et al. (2017) Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease. Am J Hum Genet 100:940-953
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Kang, Hyun Mi; Huang, Shizheng; Reidy, Kimberly et al. (2016) Sox9-Positive Progenitor Cells Play a Key Role in Renal Tubule Epithelial Regeneration in Mice. Cell Rep 14:861-871
Teumer, Alexander; Tin, Adrienne; Sorice, Rossella et al. (2016) Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes. Diabetes 65:803-17
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Edeling, Maria; Ragi, Grace; Huang, Shizheng et al. (2016) Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog. Nat Rev Nephrol 12:426-39

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