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

项目摘要/摘要 在美国和世界各地，肥胖正在成为一项重大的公共卫生挑战。它 与几种共病相关，包括心血管疾病和代谢综合征。 此外，流行病学数据表明肥胖和癌症之间有很强的联系；然而， 肥胖症和这些病理状况之间的机械联系仍然不完全。 具体地说，胰岛素抵抗的特征是全身对胰岛素的敏感性减弱，并可能 会导致循环中游离脂肪酸(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，并改变微调的调节 葡萄糖、脂肪和整体能量止血。因此，肥胖是可预防的病理性疾病的核心 由于直接引发代谢紊乱和相关的炎症反应而导致的情况。 重要的是，阐明新的代谢调节因子和血管生成调节因子可能提供独特的见解。 依赖于这些过程的疾病状况，如心血管疾病和癌症。 代谢和细胞能量学的研究包括骨骼肌、脂肪和肝脏。 细胞被赋予这些组织在脂质利用和储存方面的突出作用。然而， 血管靶点对代谢综合征的反应或贡献，包括肥胖- 煽动的骚乱仍不清楚。在提议的“血管反应目标”的结合点是 跨膜神经粘蛋白-1(Nrp1)受体。我们假设肥胖和随之而来的增加 循环中的游离脂肪酸促进Nrp1的表达和与胰岛素底物的相互作用，从而 血管Nrp1的功能。

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.