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

点击翻译按钮获取中文摘要

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.