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

阐明血管神经毡蛋白 1 (NRP1) 对与胰岛素底物的新相互作用的反应功能

• 批准号: 10550186
• 负责人: Ye Ding
• 金额: $ 39万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10550186
• 关键词: Adipocytes; Adipose tissue; Aorta; Attenuated; Binding; Binding Sites; Blood Vessels; Cancer cell line; Cardiovascular Diseases; Cell Line; Cells; Cholesterol; Cytoplasm; Cytoplasmic Tail; Diet; Disease; Docking; Dose; Endothelium; Epidermal Growth Factor Receptor; Extracellular Domain; Fluorescein-5-isothiocyanate; Functional disorder; Glucose tolerance test; Glycoproteins; Growth Factor; Hemostatic function; Hepatocyte; High Fat Diet; High-Risk Cancer; Hypoxia; In Vitro; Incidence; Inflammatory Response; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like Growth Factor I; KDR gene; Knockout Mice; Label; Link; Lipids; Liver; MET gene; Malignant Neoplasms; Measurement; Mediating; Membrane; Metabolic; Metabolic syndrome; Metabolism; Mus; Muscle Fibers; Neuropilin-1; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Pathologic; Phosphotransferases; Physiology; Play; Process; Proteins; Public Health; Receptor Protein-Tyrosine Kinases; Role; Signal Pathway; Signal Transduction; Site; Testing; Time; Tissues; Transfection; Triglycerides; Tumor Angiogenesis; United States; Up-Regulation; angiogenesis; blood glucose regulation; comorbidity; epidemiologic data; in vivo; insight; insulin receptor substrate 1 protein; insulin tolerance; metabolic abnormality assessment; mouse model; novel; protein expression; receptor; response; vascular contributions

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.

项目摘要/摘要 肥胖症正在美国以及世界各地引起的重大公共卫生挑战。它 与几种合并症有关，包括心血管疾病和代谢综合症。 此外，流行病学数据表明肥胖与癌症之间存在牢固的联系。然而， 肥胖与这些病理状况之间的机械连接仍然不完整。 具体而言，胰岛素抵抗的特征是全身对胰岛素的敏感性减弱，可能 导致循环游离脂肪酸（FFA）的水平升高。必需的代谢功能和 在这种情况下的信号通路失调，并改变了对 葡萄糖，脂质和总能量止血。因此，肥胖对于可预防的病理是核心 由于直接启动代谢扰动和相关炎症反应而引起的条件。 重要的是，阐明新型代谢以及血管生成调节剂可能会提供独特的见解 疾病状况，例如心血管疾病和取决于这些过程的癌症。 有关代谢和细胞能量学的研究包括骨骼肌，脂肪和肝 这些组织在脂质利用和储存方面起着显着作用的细胞。但是， 血管靶标在代谢综合征方面的反应或贡献，包括肥胖症 煽动的扰动尚不清楚。在拟议的“血管反应靶标”的联系中 跨膜，Neuropilin-1（NRP1）受体。我们假设肥胖和随之增加 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。