Angiogenic Signals in Diabetic Complications

糖尿病并发症中的血管生成信号

• 批准号: 7896044
• 负责人: THOMAS M COFFMAN
• 金额: $ 11.04万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-05 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896044
• 关键词: Albuminuria; Angiogenic Factor; Blood Vessels; Cardiac; Cell Lineage; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Genetic; Goals; Growth; Human; Individual; Kidney; Kidney Diseases; Link; Modeling; Modification; Mus; Organ; Pathogenesis; Pathology; Pathway interactions; Peripheral; Peripheral arterial disease; Property; Retinal Diseases; Shapes; Signal Pathway; Signal Transduction; Skeletal Muscle; Tissues; Vascular Diseases; Vascular Endothelial Growth Factors; angiogenesis; diabetic; mouse model; response

In humans with diabetes, abnormal angiogenesis contributes to the development of end-organ damage. In this regard, "excessive" angiogenesis and increased activity of the vascular endothelial growth factor (VEGF) signaling pathway have been associated with diabetic complications such as retinopathy. In contrast, an inadequate angiogenesis response with a reduced capacity to promote collateral blood vessel growth in cardiac and particularly peripheral skeletal muscle result in more severe manifestations of vascular disease in diabetes. However, the mechanisms responsible for the loss of control of angiogenesis in diabetes and how this dysregulation modulates tissue pathology are not clear. We hypothesize that abnormal signaling in VEGF-associated pathways is a critical factor in the pathogenesis of diabetic complications including peripheral artery disease (PAD) and nephropathy. Furthermore, we posit that distinct properties of individual tissues determine the effects of diabetes on the local angiogenesis response, shaping the resulting pathology. Accordingly, to develop better models of diabetic PAD and nephropathy, we will generate mouse lines with inducible alterations of angiogenic signaling pathways targeted to specific cell lineages in blood vessels, skeletal muscle and kidney. Because both enhanced and diminished VEGF activities have independently been associated with diabetic complications, we will produce models with up- or down-regulated angiogenic signaling. The long-term goals of our studies are: (1) To understand how alterations in angiogenic factors contribute to the development of diabetic complications and (2) To develop mouse models of diabetic PAD and nephropathy that more faithfully reproduce the respective human conditions. To achieve these goals we propose the following specific aims: 1.To develop mouse models with genetic modifications of key signaling pathways linked to angiogenesis. 2. To determine the effects of diabetes on angiogenic signaling in a well-established model of peripheral artery disease. 3. To define the consequences of altered angiogenic signaling on the development of albuminuria and nephropathy in diabetes.

在糖尿病患者中，血管生成异常有助于终器官的发育