Elucidating Vascular Neuropilin 1 (NRP1) Functions in Response to Novel Interactions with Insulin Substrates

项目概要/摘要 肥胖正在成为美国和世界各地的一个主要公共卫生挑战。它 与包括心血管疾病和代谢综合征在内的几种合并症相关。 此外，流行病学数据表明肥胖和癌症之间存在密切联系;然而， 肥胖和这些病理状况之间的机械联系仍然不完整。 具体地，胰岛素抵抗的特征在于全身对胰岛素的敏感性减弱，并且可能 导致循环游离脂肪酸（FFAs）水平升高。基本代谢功能和 在这种情况下，信号通路变得失调，并改变了对细胞的精细调节。 血糖、血脂和总能量止血。因此，肥胖是可预防的病理性 由于代谢紊乱和相关炎症反应的直接刺激而引起的病症。 重要的是，阐明新的代谢，以及血管生成调节可能会提供独特的见解 疾病状况，如心血管疾病和癌症，依赖于这些过程。 对代谢和细胞能量学的研究包括骨骼肌、脂肪和肝脏 这些组织在脂质利用和储存方面发挥着重要作用。但 血管靶点对代谢综合征（包括肥胖症）的反应或贡献- 煽动的扰动仍不清楚。拟议的"血管反应目标"的核心是 跨膜，神经纤毛蛋白-1（Nrp1）受体。我们假设肥胖和伴随的增加 循环FFA促进Nrp1与胰岛素底物的表达和相互作用， 血管Nrp1功能。

Project Summary/Abstract Obesity is emerging a major public health challenge in the United States, and around the world. It correlates with several comorbidities including, cardiovascular diseases and metabolic syndromes. Additionally, epidemiological data suggest strong links between obesity and cancer; however, mechanistic connections between obesity and these pathological conditions remain incomplete. Specifically, insulin resistance is characterized by attenuated whole-body sensitivity to insulin and may result in elevated levels of circulating free fatty acids (FFAs). Essential metabolic functions and signaling pathways under this condition becomes dysregulated, and alter finely-tuned regulation of glucose, lipid and overall energy hemostasis. Therefore, obesity is central to preventable pathological conditions due to direct instigation of metabolic perturbations and associated inflammatory responses. Importantly, elucidating novel metabolic, as well as angiogenic regulators may provide unique insight of disease conditions, such as cardiovascular diseases and cancer that depend on these processes. Studies on metabolism and cellular energetics have included skeletal muscles, adipose and hepatic cells given prominent roles these tissues play with respect to lipid utilization and storage. However, the response or contributions of vascular targets with respect to metabolic syndromes, including obesity- instigated perturbations remain unclear. At the nexus of proposed `vascular response target' is transmembrane, neuropilin-1 (Nrp1) receptor. We hypothesize that obesity and concomitant increase of circulating FFAs promote the expression and interaction of Nrp1 with insulin substrates, which vascular Nrp1 functions.