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.

心血管疾病是美国死亡的主要原因。周围动脉疾病 （PAD）通常认为病理本质上是血管的，并且与组织底物有关 送货。骨骼肌使用异常的底物利用很少是针对研究的，但可以 对疾病病理的贡献平均或更大。当前的应用程序解决了需要 对内皮和骨骼肌细胞在反应中的特定作用的批判性理解 心血管疾病缺血/缺氧。该项目的指导阶段的目标是进步 对遗传影响对PAD病理学的机械理解。上一个和初步数据 支持Bcl-2相关的Athanogene，Bag3中的多态性的观念，它调节了反应 外周肢体组织到缺血/缺氧侮辱。我们假设Bag3是 内皮和骨骼肌细胞对缺血的反应以及Bag3中的多态性 在此侮辱中更改其功能。我们建议在以下特定目的中检查此主题：1） 确定BAG3在骨骼肌和内皮细胞对低氧的特定反应中的作用 侮辱和2）确定BAG3多态性对骨骼肌肉和内皮细胞的影响 响应缺血/低氧损伤的功能。该应用程序的这个阶段将提供培训 肌肉血管生物学将有助于将我的肌肉生物学背景整合到此 协调的研究重点。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心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的反应，包括周围 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传导层流相互作用，以传播细胞存活和 /或 从缓存的侮辱中恢复。我建议在独立阶段检查这个话题 在以下目的中奖励：3）确定调节相互作用的新因素和信号通路 心血管疾病和血管中肢体肌肉脉管系统和骨骼肌纤维 重塑。指导和独立阶段提出的研究结果将 显着促进当前对心血管疾病相关的肢体病理学的知识。