Notch and Insulin Signaling Interactions in Adipogenesis and Angiogenesis

描述(由申请人提供)： 糖尿病患者通常会出现肥胖和血管病变。导致糖尿病并发症的分子机制仍有待阐明。在过去的两年里，我一直在评估Notch4基因敲除小鼠的出生后缺陷。这些分析表明，Notch4突变小鼠出现了糖尿病的特征：1)皮下脂肪急剧增加所见的早发性肥胖，以及2)视网膜血管中周细胞含量减少，使人想起糖尿病视网膜病变。在与Accili博士的合作中，我们发现Notch和Foxo1，一种胰岛素信号的转录调节因子，合作调控脂肪生成和血管生成。Notch1、Notch 1/Notch4或Foxo1基因缺陷的小鼠在子宫中死于血管生成缺陷。这些数据使我们假设，Notch信号失控与糖尿病、肥胖和血管病变有关。建议的目标是检验这一假说，并确定Notch和胰岛素信号相互作用在脂肪生成和血管生成中的作用。小鼠模型将被用来通过基因操作改变Notch、Foxo1和胰岛素受体的活性。Notch4和胰岛素受体基因敲除小鼠以及来自这些小鼠的胚胎成纤维细胞将评估脂肪生成和代谢功能障碍。胚胎和视网膜血管生成将在Notch1、Notch4和/或Foxo1单倍体缺陷的小鼠中进行评估。最后，将在低氧驱动的视网膜血管生成小鼠模型中评估Notch和Foxo1信号在增殖性视网膜病变中的作用。 我的职业目标是成为糖尿病研究领域的一名独立科学调查员。我将运用我在遗传学、分子生物学和发育生物学方面的背景来了解糖尿病和糖尿病并发症的发展。Naomi Berrie糖尿病中心、纽约肥胖研究中心和哥伦比亚糖尿病和内分泌研究中心(我的共同导师Accili博士是该中心的主任)是治疗糖尿病和支持临床转化研究的主要机构。我的长期研究目标是研究Notch/Foxo1在糖尿病肥胖和血管病理中的作用，如中风、伤口愈合、缺血组织的新生血管形成和增殖性视网膜病变。我预计这些研究将增进对糖尿病的了解，为我的研究生涯的发展提供一个框架，并可能导致治疗糖尿病的新药。

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.