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.

糖尿病患者经常出现肥胖和血管病理。贡献的分子机制 糖尿病并发症仍有待阐明。在过去的两年中，我一直在评估Notch4 敲除鼠后缺陷的小鼠。这些分析表明，Notch4突变小鼠发展了标志 糖尿病：1）皮下脂肪的显着增加和2）降低周细胞的早期发作肥胖症 视网膜血管中的含量让人联想到糖尿病性视网膜病。在与Accili博士合作的情况下，我们有 发现Notch和Foxol是胰岛素信号传导的转录调节器，Cooperateto调节 掺杂和血管生成。缺乏Notchl，Notch1/Notch4或Foxol的小鼠在子宫内死亡 血管生成缺陷。这些数据导致我们假设的Notch信号失调有助于 糖尿病肥胖和脉管病理学。建议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。鼠标模型将是 用于通过遗传操纵来改变缺口，狐醇和胰岛素受体活性。脂肪形成和 代谢功能障碍将在Notch4和胰岛素受体敲除小鼠和胚胎中评估 源自这些小鼠的成纤维细胞。将在小鼠中评估胚胎和视网膜血管生成 可用于Notchl，Notch4和/或Foxol的单倍弹性。最后，Notch和Foxol信号的功能 增殖性视网膜病将在缺氧驱动的视网膜血管生成小鼠模型中评估。 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 将应用我的遗传学，分子和发育生物学的背景来了解发展 糖尿病和糖尿病并发症。纽约肥胖研究的Naomi Berrie糖尿病中心 中心和哥伦比亚糖尿病和内分泌研究中心，我的同事Accili博士是 主任是治疗糖尿病的主要机构和临床转化研究的支持。我的 ONG - 期限研究目标是研究Notch/Foxol在糖尿病肥胖症中的作用 血管病理学，例如中风，伤口愈合，缺血组织的新血管化和增殖 视网膜病。我预计这些研究将增强对糖尿病的理解，为 我的研究生涯的发展，可能会导致新药治疗糖尿病患者。