Notch and Insulin Signaling Interactions in Adipogenesis and Angiogenesis

Notch 和胰岛素信号在脂肪生成和血管生成中的相互作用

• 批准号: 7082710
• 负责人: CARRIE J. SHAWBER
• 金额: $ 10.49万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-10 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082710
• 关键词: adipocytes; angiogenesis; biological signal transduction; cell differentiation; cell surface receptors; diabetes mellitus; disease /disorder model; fibroblasts; genetic manipulation; genetic transcription; genetically modified animals; immunocytochemistry; insulin; insulin receptor; laboratory mouse; medical complication; metabolism disorder; obesity; phenotype; protein protein interaction; protein structure function; retina; vascular endothelial growth factors

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.

描述（由申请人提供）： 糖尿病患者经常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基因敲除小鼠的产后缺陷。这些分析表明，Notch4 突变小鼠出现糖尿病的特征：1）早发性肥胖，表现为皮下脂肪急剧增加；2）视网膜脉管系统周细胞含量减少，让人联想到糖尿病视网膜病变。我们与 Accili 博士合作，发现 Notch 和 Foxo1（胰岛素信号传导的转录调节因子）协同调节脂肪生成和血管生成。 Notch1、Notch 1/Notch4 或 Foxo1 缺陷的小鼠会在子宫内死亡，并伴有血管生成缺陷。这些数据使我们推测，Notch 信号传导失调会导致糖尿病性肥胖和血管病理。该提案的目的是检验这一假设并定义 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。小鼠模型将用于通过基因操作改变 Notch、Foxo1 和胰岛素受体活性。将在 Notch4 和胰岛素受体敲除小鼠以及源自这些小鼠的胚胎成纤维细胞中评估脂肪生成和代谢功能障碍。将在Notch1、Notch4和/或Foxo1单倍体不足的小鼠中评估胚胎和视网膜血管生成。最后，将在缺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功能。 我的职业目标是成为糖尿病研究领域的独立科学研究者。我将运用我在遗传学、分子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。内奥米·贝里糖尿病中心、纽约肥胖研究中心和哥伦比亚糖尿病和内分泌研究中心（我的搭档阿奇利博士担任主任）是治疗糖尿病和支持临床转化研究的首要机构。我的长期研究目标是研究 Notch/Foxo1 在糖尿病性肥胖和血管病理学中的作用，例如中风、伤口愈合、缺血组织的新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框架，并可能带来治疗糖尿病的新药。