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: 7221252
• 负责人: CARRIE J. SHAWBER
• 金额: $ 10.71万
• 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/7221252
• 关键词: Adipocytes; Adipose tissue; Affect; Biological Assay; Birth; Blood Vessels; Blood capillaries; Cells; Clinical; Collaborations; Complications of Diabetes Mellitus; Data; Defect; Dermal; Development; Developmental Biology; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Retinopathy; Dominant-Negative Mutation; Embryo; Embryonic Development; Endocrinology; Evaluation; Eye; Fatty acid glycerol esters; Fibroblasts; Functional disorder; Goals; Growth; Hormones; Hypertrophy; Hypoxia; Institutes; Insulin Receptor; Knockout Mice; Lead; Link; Mentors; Metabolic; Metabolism; Modeling; Molecular; Molecular Genetics; Mus; Mutant Strains Mice; New York; Obesity; Pathology; Pathway interactions; Patients; Pericytes; Pharmaceutical Preparations; Phenotype; Physiologic Neovascularization; Principal Investigator; Research; Research Personnel; Retina; Retinal; Retinal Diseases; Retinal Neovascularization; Role; Signal Transduction; Site; Smooth Muscle Myocytes; Stroke; Tissues; Translational Research; Vascular Endothelial Growth Factors; Vascular remodeling; Vascularization; Venous; Wound Healing; adipocyte differentiation; angiogenesis; capillary; cardiogenesis; career; density; diabetic; early onset; genetic manipulation; in utero; in vivo; insulin signaling; lipid biosynthesis; mouse model; mutant; neovascularization; notch protein; postnatal; programs; retinal angiogenesis; subcutaneous

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理。导致糖尿病并发症的分子机制仍有待阐明。在过去的两年中，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突变小鼠会发展出糖尿病的标志：1）皮下脂肪的急剧增加，以及2）视网膜脉管体中周围的周细胞含量降低，让人联想到糖尿病性视网膜病变。与Accili博士合作，我们发现Notch和FoxO1是胰岛素信号传导的转录调节剂，合作调节脂肪生成和血管生成。缺乏缺乏Notch1，Notch 1/Notch4或FoxO1的小鼠在子宫内死亡。这些数据使我们假设失调的Notch信号传导有助于糖尿病肥胖和血管病理学。该建议的目标是检查这一假设，并定义Notch和胰岛素信号传导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遗传操作来改变Notch，FOXO1和胰岛素受体活性。将在Notch4和胰岛素受体敲除小鼠和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。在Notch1，Notch4和/或FoxO1的小鼠中，将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信号传导在增殖性视网膜病中的功能。 我的职业目标是成为糖尿病研究领域的独立科学研究者。我将在遗传学，分子和发育生物学上应用我的背景，以了解糖尿病和糖尿病并发症的发展。 Naomi Berrie糖尿病中心，纽约肥胖研究中心以及哥伦比亚糖尿病和内分泌研究中心，我的同事Accili博士是主任，是糖尿病治疗和临床翻译研究支持的首要研究所。我的长期研究目标是研究Notch/FoxO1在糖尿病肥胖和血管病理学中的作用，例如中风，伤口愈合，缺血性组织的新血管化和增殖性视网膜病。我预计这些研究将增强对糖尿病的理解，为我的研究职业发展提供框架，并可能导致治疗糖尿病患者的新药。