Angiogenic Signals in Diabetic Complications

描述(由申请人提供)： 在糖尿病患者中，异常的血管生成有助于终末器官损伤的发展。在这方面，“过度的”血管生成和血管内皮生长因子(VEGF)信号通路的活性增加与糖尿病并发症(如视网膜病变)有关。相反，血管生成反应不足，促进心脏侧支血管生长的能力降低，尤其是外周骨骼肌，导致糖尿病血管疾病的更严重表现。然而，糖尿病血管生成失控的机制以及这种失调如何调节组织病理尚不清楚。我们推测，血管内皮生长因子相关信号通路的异常是糖尿病并发症发生的关键因素，包括外周动脉疾病(PAD)和肾病。此外，我们假设，个别组织的不同属性决定了糖尿病对局部血管生成反应的影响，从而塑造了由此产生的病理。因此，为了开发更好的糖尿病PAD和肾病模型，我们将产生针对血管、骨骼肌和肾脏中特定细胞系的血管生成信号通路的可诱导改变的小鼠系。由于血管内皮生长因子活性的增强和减弱都与糖尿病并发症独立相关，因此我们将建立上调或下调血管生成信号的模型。我们研究的长期目标是：(1)了解血管生成因子的变化如何有助于糖尿病并发症的发展，以及(2)建立更真实地再现各自人类状况的糖尿病垫和肾病的小鼠模型。为了实现这些目标，我们提出了以下具体目标：1.建立与血管生成相关的关键信号通路的基因修饰的小鼠模型。2.在已建立的外周动脉疾病模型中，确定糖尿病对血管生成信号的影响。3.明确血管生成信号改变在糖尿病蛋白尿和肾病发生发展中的作用。

DESCRIPTION (provided by applicant): 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.