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.

在患有糖尿病的人中，异常的血管生成有助于最终器官的发展 损害。在这方面，血管内皮的“过度”血管生成和活动增加 生长因子（VEGF）信号通路与糖尿病并发症（例如 视网膜病。相反，血管生成反应不足，能力降低 心脏，尤其是外周骨骼肌的副血管生长导致更多 糖尿病血管疾病的严重表现。但是，负责的机制 糖尿病中血管生成的控制丧失以及这种失调如何调节组织 病理尚不清楚。我们假设VEGF相关途径中的异常信号传导是 包括周围动脉疾病（PAD）的糖尿病并发症发病机理的关键因素 和肾病。此外，我们认为单个组织的不同特性决定了 糖尿病对局部血管生成反应的影响，塑造了所得病理。因此， 为了开发更好的糖尿病垫和肾病模型，我们将与 针对血液中特定细胞谱系的血管生成信号通路的诱导诱导改变 血管，骨骼肌和肾脏。因为增强和减少的VEGF活动都有 我们将独立与糖尿病并发症相关，我们将生产具有上或上的模型 下调的血管生成信号传导。我们研究的长期目标是：（1）了解 血管生成因子的改变如何有助于糖尿病并发症的发展和（2） 开发糖尿病垫和肾病的小鼠模型，以更忠实地再现 各自的人类条件。为了实现这些目标，我们提出以下特定目标：1。 开发具有与血管生成有关的关键信号通路的遗传修饰的小鼠模型。 2。确定糖尿病对良好模型中血管生成信号传导的影响 周围动脉疾病。 3。定义变化的血管生成信号的后果 糖尿病中蛋白尿和肾病的发育。