Peripheral endothelial and muscle cell pathology in cardiovascular disease

心血管疾病中的外周内皮和肌肉细胞病理学

• 批准号: 8780799
• 负责人: JOSEPH Matthew MCCLUNG
• 金额: $ 24.9万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8780799
• 关键词: Address; Anatomy; Animals; Apoptosis; Atrophic; Attenuated; Autophagocytosis; Award; BCL2 gene; Binding Proteins; Biological; Biology; Blood Vessels; Brain Hypoxia-Ischemia; Cardiovascular Diseases; Cause of Death; Cell physiology; Cellular Stress; Childhood; Chromosomes, Human, Pair 7; Data; Dependovirus; Development; Diabetes Mellitus; Disease; Endothelial Cells; Exercise; Foundations; Funding; Genetic; Genetic Polymorphism; Goals; Graduate Education; Human; Hypoxia; In Vitro; Individual; Intermittent Claudication; Investigation; Ischemia; Isolated limb perfusion; Knowledge; Learning; Light; Limb structure; Link; Mechanical Stress; Mediating; Mentors; Mitochondria; Molecular Chaperones; Molecular and Cellular Biology; Morbidity - disease rate; Mouse Strains; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscular Dystrophies; Mutation; Nature; Necrosis; Nutrient; Outcome; Outcomes Research; Pain; Pathology; Patients; Perfusion; Perinatal; Peripheral; Peripheral arterial disease; Phase; Physiological; Physiology; Protein Biosynthesis; Proteins; Proteolysis; Proteomics; Quantitative Trait Loci; Recovery; Regulation; Research; Research Personnel; Rest; Role; Scientist; Signal Pathway; Signal Transduction; Skeletal Muscle; Solid; Stress; System; Testing; Tissues; Training; Ubiquitin; Ulcer; United States; Vascular Endothelial Cell; Vascular remodeling; career; cell type; deprivation; gain of function; in vivo; loss of function; mortality; multicatalytic endopeptidase complex; novel; overexpression; patient population; post-doctoral training; protein degradation; regenerative; response; skeletal; skeletal muscle wasting

Cardiovascular disease is the leading cause of death in the United States. Peripheral arterial disease (PAD) pathology is commonly assumed to be vascular in nature and associated with tissue substrate delivery. Abnormal substrate utilization by skeletal muscle is seldom targeted for investigation, but may contribute equally or greater to disease pathology. The current application addresses the need for critical understanding of the specific roles of endothelial and skeletal muscle cells in the response to cardiovascular disease ischemia/hypoxia. The goal of the Mentored phase of this project is to advance the mechanistic understanding of genetic influence on PAD pathology. Previous and preliminary data support the idea that polymorphisms in the Bcl-2 associated athanogene, BAG3, regulate the response of peripheral limb tissue to ischemic/hypoxic insult. We hypothesize that BAG3 is a critical regulator of the response of both endothelial and skeletal muscle cells to ischemia and that polymorphisms in BAG3 alter its function during this insult. We propose to examine this topic in the following specific aims: 1) determine the role of BAG3 in the specific responses of skeletal muscle and endothelial cells to hypoxic insult, and 2) determine the effect of BAG3 polymorphisms on skeletal muscle and endothelial cell function in response to ischemia/hypoxic insult. This phase of the application will provide training in muscle vascular biology that will facilitate the integration of my muscle biology background into this coordinated research focus. My long-term career goal is to become a successful independent scientist investigating how the dynamic interactions between the vasculature and skeletal myocytes regulate the responses of limb muscle in both physiological and pathophysiological states, including peripheral artery disease, diabetes mellitus, and exercise. My overall hypothesis is that vascular endothelial cells and skeletal muscle interact via biological signaling cascades to propagate cellular survival and or recovery from cachectic insult. I propose to examine this topic in the Independence phase of this award in the following aim: 3) determine novel factors and signaling pathways regulating the interaction of limb muscle vasculature and skeletal myofibers during cardiovascular disease muscle and vascular remodeling. The outcomes of the research proposed in both Mentored and Independent phases will significantly advance the current knowledge of cardiovascular disease associated limb pathology.

心血管疾病是美国的首要死因。周围动脉疾病 (PAD) 病理学通常被认为本质上是血管性的并且与组织基质有关 送货。骨骼肌对底物的异常利用很少成为研究的目标，但可能 对疾病病理学的贡献相同或更大。当前的应用程序解决了以下需求 批判性地理解内皮细胞和骨骼肌细胞在响应中的具体作用 心血管疾病缺血/缺氧。该项目指导阶段的目标是推进 遗传对 PAD 病理学影响的机制理解。先前和初步数据 支持 Bcl-2 相关的 athanogene、BAG3 中的多态性调节反应的观点 周围肢体组织缺血/缺氧损伤。我们假设 BAG3 是 内皮细胞和骨骼肌细胞对缺血的反应以及 BAG3 的多态性 在这次侮辱期间改变其功能。我们建议按照以下具体目标研究该主题：1） 确定 BAG3 在骨骼肌和内皮细胞对缺氧的特异性反应中的作用 损伤，2) 确定 BAG3 多态性对骨骼肌和内皮细胞的影响 响应缺血/缺氧损伤的功能。此阶段的申请将提供以下方面的培训 肌肉血管生物学，这将有助于将我的肌肉生物学背景融入其中 协调研究重点。我的长期职业目标是成为一名成功的独立科学家 研究脉管系统和骨骼肌细胞之间的动态相互作用如何调节 肢体肌肉在生理和病理生理状态下的反应，包括外周 动脉疾病、糖尿病和运动。我的总体假设是血管内皮细胞 和骨骼肌通过生物信号级联相互作用以促进细胞存活和/或 从恶病质侮辱中恢复过来。我建议在独立阶段研究这个主题 奖励以下目标：3）确定调节相互作用的新因子和信号通路 心血管疾病期间肢体肌肉脉管系统和骨骼肌纤维的变化 肌肉和血管 重塑。在指导和独立阶段提出的研究结果将 显着提高了当前对心血管疾病相关肢体病理学的认识。