Vascular Insulin Resistance in Obesity: Role of Endoplasmic Reticulum Stress

肥胖症中的血管胰岛素抵抗：内质网应激的作用

• 批准号: 9178082
• 负责人: Jaume Padilla
• 金额: $ 14.1万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-15 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178082
• 关键词: Adipose tissue; Age; Animal Model; Attenuated; Biological Sciences; Biology; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Chemicals; Childhood; Clinical; Conditioned Culture Media; Contralateral; Diabetes Mellitus; Disease; Doctor of Philosophy; Endoplasmic Reticulum; Endothelin-1; Ensure; Environment; Epidemic; Equilibrium; Exercise Physiology; Exhibits; Faculty; Family suidae; Funding; GRP78 gene; Genetic; Goals; Health; Home environment; Human; Impairment; In Vitro; Inflammatory; Insulin; Insulin Resistance; K-Series Research Career Programs; Lead; Link; Mediating; Mentors; Metabolic Diseases; Metabolism; Missouri; Modeling; Molecular; Molecular Chaperones; Nature; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral Administration; Pathogenesis; Patients; Peripheral; Pharmacology; Physical activity; Physicians; Positioning Attribute; Preparation; Prevalence; Proteomics; Readiness; Recording of previous events; Research; Research Personnel; Research Training; Resources; Role; Science; Skeletal Muscle; Techniques; Testing; Thinness; Tissue Harvesting; Training; Transfection; Translational Research; United States; United States National Institutes of Health; Universities; Vascular Diseases; Vasodilation; Work; arteriole; blood glucose regulation; career; career development; cytokine; dalton; endoplasmic reticulum stress; endothelial dysfunction; experimental study; femoral artery; gain of function; glucose uptake; in vivo; insulin signaling; internal control; loss of function; misfolded protein; novel therapeutics; overexpression; prevent; programs; skills; tauroursodeoxycholic acid; tool; translational research program; western diet

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)

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传导受损和心血管疾病的机制。在肥胖症中，胰岛素刺激的流向骨骼肌的血流是有限的，这减弱了葡萄糖摄取，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。这项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设。肥胖引起的血管内质网应激和血管胰岛素抵抗可能与血管周围脂肪组织（PVAT）局部分泌炎性细胞因子有关。使用西方饮食诱导的肥胖症的良好建立的猪模型，Aim 1将测试肥胖症相关的血管ER应激是否是导致胰岛素刺激的血管舒张受损的一氧化氮和内皮素-1之间的失衡的基础。目标2将确定肥胖骨骼肌PVAT是否会引起血管ER应激，从而导致胰岛素刺激的血管舒张受损。最后，目标3将研究是否在体内遗传和化学增强ER功能可以恢复受损的胰岛素刺激的血管舒张与肥胖相关。这项在猪中提出的工作的贡献是重要的，因为靶向ER应激可能是一种新的治疗策略，以纠正血管胰岛素抵抗，并最终预防/治疗肥胖引起的代谢和心血管疾病。密苏里州大学（MU）校园在心血管科学、代谢和运动生理学方面有着杰出的研究历史，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、国家猪资源与研究中心的所在地，这些中心是本项目的资源。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，我将与大量的高级研究人员互动，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研究者。James R. Sowers医学博士将是我的主要导师，Frank W.布斯博士将担任我的共同导师Sowers博士是一名临床医生，也是一名研究人员，擅长血管胰岛素作用和心脏代谢疾病。布斯博士在脂肪组织生物学和体育活动方面有专长。我们一起组建了一个全面的研究培训计划和合作者团队，这将有助于收购 新的分子技术（即，体内腺病毒转染、蛋白质组学）以及涉及体外制备分离的完整小动脉的技术，以增强 进行机理研究。这些额外的技能与我早期在人类血管研究的背景相结合，将有助于我建立一个研究计划的长期目标，能够使用肥胖/2型糖尿病的动物模型以及人类患者进行体外和体内机制和转化研究。简而言之，我的培训计划所提供的额外的技术，学术和职业发展将使我处于一个理想的位置，成功地启动一个富有成效的，独立的和转化的研究计划。这个NIH K 01申请代表了我作为一名年轻的早期研究者职业发展的下一个合乎逻辑的步骤，并将为我的第一个R 01申请奠定基础。(End摘要）