Notch and Insulin Signaling Interactions in Adipogenesis and Angiogenesis

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DESCRIPTION (provided by applicant): Diabetic patients often develop obesity and vascular pathologies. The molecular mechanisms that contribute to diabetic complications remain to be elucidated. In the past two years, I have been evaluating Notch4 knockout mice for postnatal defects. These analyses revealed that Notch4 mutant mice develop hallmarks of diabetes: 1) early onset obesity as seen by a dramatic increase in subcutaneous fat, and 2) reduced pericyte content in retinal vasculature reminiscent of diabetic retinopathy. In collaboration with Dr. Accili, we have found that Notch and Foxo1, a transcriptional regulator of insulin signaling, cooperate to regulate adipogenesis and angiogenesis. Mice deficient for Notch1, Notch 1/Notch4, or Foxo1 die in utero with angiogenic defects. These data lead us to hypothesize that dysregulated Notch signaling contributes to diabetic obesity and vasculopathologies. The proposal objective is to examine this hypothesis and define the roles of Notch and insulin signaling interactions in adipogenesis and angiogenesis. Mouse models will be used to alter Notch, Foxo1, and insulin receptor activity via genetic manipulation. Adipogenesis and metabolic dysfunction will be evaluated in Notch4 and insulin receptor knockout mice and embryonic fibroblasts derived from these mice. Embryonic and retinal angiogenesis will be evaluated in mice haploinsufficient for Notch1, Notch4 and/or Foxo1. Finally, the function of Notch and Foxo1 signaling in proliferative retinopathy will be evaluated in a hypoxia-driven retinal angiogenesis mouse model. My career goals are to become an independent scientific investigator in the field of diabetic research. I will apply my background in genetics, molecular and developmental biology to understand the development of diabetes and diabetic complications. The Naomi Berrie Diabetes Center, The New York Obesity Research Center and the Columbia Diabetes and Endocrinology Research Center, of which my co-mentor Dr. Accili is Director, are premier institutes for the treatment of diabetes and support of clinical translational research. My long-term research goals are to investigate the role of Notch/Foxo1 in diabetic obesity and vasculopathologies, such as stroke, wound healing, neo-vascularization of ischemic tissue and proliferative retinopathy. I anticipate that these studies will enhance understanding of diabetes, provide a framework for the development of my research career and may lead to new drugs for the treatment of diabetics.