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: 7394982
• 负责人: CARRIE J. SHAWBER
• 金额: $ 11.11万
• 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/7394982
• 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

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 Foxol, a transcriptional regulator of insulin signaling, cooperateto regulate adipogenesis and angiogenesis. Mice deficient for Notchl, Notch1/Notch4, or Foxol die in utero with angiogenic defects. These data lead us to hypothesizethat 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, Foxol, 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 Notchl, Notch4 and/or Foxol. Finally, the function of Notch and Foxol 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 ong-term research goals are to investigate the role of Notch/Foxol 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.

糖尿病患者通常会出现肥胖和血管病变。这些分子机制 糖尿病并发症仍有待阐明。在过去的两年里，我一直在评估Notch 4 基因敲除小鼠的出生后缺陷。这些分析表明，Notch 4突变小鼠发展了 糖尿病：1）早发性肥胖，表现为皮下脂肪急剧增加，2）周细胞减少 视网膜血管中的内容物使人联想到糖尿病视网膜病变。与Accili博士合作，我们 发现Notch和Foxol，一种胰岛素信号的转录调节因子， 脂肪生成和血管生成。Notch 1、Notch 1/Notch 4或Foxol缺陷的小鼠在子宫内死亡， 血管生成缺陷。这些数据使我们假设Notch信号失调有助于 糖尿病性肥胖和血管病变。该提案的目的是检验这一假设，并确定 Notch和胰岛素信号相互作用在脂肪形成和血管生成中的作用。小鼠模型将 用于通过遗传操作改变Notch、Foxol和胰岛素受体活性。脂肪形成和 代谢功能障碍将在Notch 4和胰岛素受体敲除小鼠和胚胎中评估。 从这些小鼠衍生的成纤维细胞。将在小鼠中评价胚胎和视网膜血管生成 Notchl、Notch 4和/或Foxol的单倍不足。最后，Notch和Foxol信号转导在肿瘤细胞中的作用 在缺氧驱动的视网膜血管生成小鼠模型中评价增殖性视网膜病。 我的职业目标是成为糖尿病研究领域的独立科学调查员。我 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知识， 糖尿病和糖尿病并发症。娜奥米·贝里糖尿病中心，纽约肥胖研究中心 中心和哥伦比亚糖尿病和内分泌学研究中心，我的共同导师阿奇利博士是 主任，是治疗糖尿病和支持临床转化研究的首要研究所。我 长期研究目标是研究Notch/Foxol在糖尿病肥胖中的作用， 血管病理学，例如中风、伤口愈合、缺血组织的新血管形成和增殖性血管形成， 视网膜病变我预计这些研究将提高对糖尿病的认识，为糖尿病的治疗提供一个框架。 我的研究事业的发展，并可能导致新的药物治疗糖尿病。