Vascular Insulin Resistance in Obesity: Role of Endoplasmic Reticulum Stress

描述（由申请人提供）：我的长期职业目标是开发一个独立的，资助的研究项目，有助于了解肥胖和2型糖尿病导致血管胰岛素信号受损和心血管疾病的机制。在肥胖中，胰岛素刺激的骨骼肌血流量受到限制，这减弱了葡萄糖的摄取，从而导致葡萄糖稳态受损。然而，胰岛素诱导的血管舒张受损的机制在很大程度上是未知的。本研究将验证内质网应激介导胰岛素刺激的骨骼肌小动脉血管舒张功能受损的假说。认为肥胖引起的血管内质网应激和血管胰岛素抵抗与血管周围脂肪组织（PVAT）局部分泌炎性细胞因子有关。利用一种成熟的西方饮食诱导的肥胖猪模型，Aim 1将测试肥胖相关的血管内质网应激是否导致一氧化氮和内皮素-1之间的失衡，从而导致胰岛素刺激的血管舒张受损。目的2将确定肥胖的骨骼肌PVAT是否会引起血管内质网应激，从而导致胰岛素刺激的血管舒张受损。最后，Aim 3将研究体内内质网功能的遗传和化学增强是否可以恢复与肥胖相关的胰岛素刺激的血管舒张受损。这项工作在猪身上的贡献是重要的，因为靶向内质网应激可能是一种新的治疗策略，可以纠正血管胰岛素抵抗，最终预防/治疗由肥胖引起的代谢和心血管疾病。密苏里大学（MU）校园在心血管科学、代谢和运动生理学的研究方面有着杰出的历史，是生命科学中心、道尔顿心血管研究中心、健康活动中心、糖尿病和心血管中心的所在地，国家猪资源与研究中心是这个项目的资源。这些中心充满了来自多个部门和部门的教师，他们积极合作，为我的独立研究提供了无与伦比的研究环境。事实上，我将与大量的高级调查员进行互动，他们不仅有助于确保成功完成拟议的研究，而且还有助于我的职业发展，因为我正在成为一名成功的独立调查员。医学博士James R. Sowers将是我的主要导师，博士Frank W. Booth将作为我的共同导师。Sowers博士是一名临床医生，也是血管胰岛素作用和心脏代谢疾病的专业研究人员。布斯博士擅长脂肪组织生物学和身体活动。我们共同组建了一个全面的研究培训计划和合作团队，以促进此次收购

DESCRIPTION (provided by applicant): My long-term career goal is to develop an independent, funded research program that contributes to understanding the mechanisms by which obesity and type 2 diabetes lead to impaired vascular insulin signaling and cardiovascular disease. In obesity, insulin-stimulated blood flow to skeletal muscle is limited and this attenuate glucose uptake, thus contributing to impaired glucose homeostasis. However, the mechanism by which insulin-induced vasodilation becomes impaired is largely unknown. The proposed study will test the hypothesis that endoplasmic reticulum (ER) stress mediates the impairment in insulin-stimulated vasodilation in skeletal muscle arterioles. It is reasoned that vascular ER stress and vascular insulin resistance caused by obesity is attributable to the local secretion of inflammatory cytokines by perivascular adipose tissue (PVAT). Using a well-established pig model of Western diet-induced obesity, Aim 1 will test if obesity-associated vascular ER stress underlies the imbalance between nitric oxide and endothlein-1 leading to impaired insulin- stimulated vasodilation. Aim 2 will then determine if obese skeletal muscle PVAT can cause vascular ER stress, thus contributing to impaired insulin-stimulated vasodilation. Finally, Aim 3 will examine whether in vivo genetic and chemical enhancement of ER function can restore impaired insulin-stimulated vasodilation associated with obesity. The contribution of this proposed work in pigs is significant as targeting ER stress may be a novel therapeutic strategy to correct vascular insulin resistance and ultimately prevent/treat metabolic and cardiovascular disease fueled by obesity. The University of Missouri (MU) campus has a distinguished history of research in cardiovascular science, metabolism, and exercise physiology and is the home for the Life Sciences Center, the Dalton Cardiovascular Research Center, the Health Activity Center, the Diabetes and Cardiovascular Center, the National Swine Resource & Research Center as resources for this project. These centers are filled with faculty from multiple departments and divisions that actively collaborate, providing an unparalleled research environment to pursue my independent research. Indeed, I will be interacting with a large number of senior investigators who will not only help ensure successful completion of the proposed studies, but also facilitate my career development as I progress toward becoming a successful independent investigator. James R. Sowers, MD, will be my primary mentor and Frank W. Booth, PhD will act as my co-mentor. Dr. Sowers is a clinical physician as well as a researcher with expertise in vascular insulin actions and cardiometabolic disease. Dr. Booth has expertise in adipose tissue biology and physical activity. Together, we have assembled a comprehensive research training plan and team of collaborators that will facilitate the acquisition of new molecular techniques (i.e., in vivo adenoviral transfection, proteomics) as well as techniques involving in vitro preparations of isolated intact arterioles to enhance my abilities to conduct mechanistic research. These additional skills combined with my earlier background in human vascular research will contribute to my long-term goal of establishing a research program with capabilities to conduct in vitro and in vivo mechanistic and translational research using animal models of obesity/type 2 diabetes as well as human patients. In short, the additional technical, academic, and career development afforded by my training plan will place me in an ideal position to successfully launch a productive, independent and translational research program. This NIH K01 application represents the next logical step in my career development as a young early investigator and will set the stage for my first R01 application. (End of Abstract)