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: 7959104
• 负责人: JOSEPH Matthew MCCLUNG
• 金额: $ 12.29万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-20 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959104
• 关键词: Address; Anatomy; Animals; Apoptosis; Atrophic; Attenuated; Autophagocytosis; Award; 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; Healed; Human; Hypoxia; In Vitro; Individual; Intermittent Claudication; Investigation; Ischemia; Isolated limb perfusion; Knowledge; Learning; Light; Limb structure; Link; Lod Score; 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; healing; in vivo; loss of function; mortality; multicatalytic endopeptidase complex; novel; overexpression; patient population; post-doctoral training; protein degradation; public health relevance; regenerative; response; skeletal; skeletal muscle wasting

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading cause of death in the United States. One of the most under-recognized aspects of cardiovascular disease is peripheral arterial disease (PAD). These studies will contribute to the mechanistic understanding of the critical role of genetic influence on PAD pathology, and aid in the development of unique, focused approaches to counteract cardiovascular disease pathology in patient populations.

描述（由申请人提供）：心血管疾病是美国的首要死因。外周动脉疾病（PAD）病理学通常被认为本质上是血管性的并且与组织基质输送相关。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产生同等或更大的影响。当前的应用解决了对内皮细胞和骨骼肌细胞在心血管疾病缺血/缺氧反应中的具体作用的批判性理解的需要。该项目指导阶段的目标是增进对遗传对 PAD 病理学影响的机制的理解。先前的初步数据支持这样的观点，即 Bcl-2 相关的 athanogene、BAG3 的多态性调节外周肢体组织对缺血/缺氧损伤的反应。我们假设 BAG3 是内皮细胞和骨骼肌细胞对缺血反应的关键调节因子，并且 BAG3 的多态性在这种损伤过程中改变了其功能。我们建议以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损伤的特异性反应中的作用，2）确定BAG3多态性对骨骼肌和内皮细胞响应缺血/缺氧损伤的功能的影响。这一阶段的申请将提供肌肉血管生物学方面的培训，这将有助于将我的肌肉生物学背景整合到这个协调的研究重点中。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/或从恶病质损伤中恢复。我建议在该奖项的独立阶段研究该主题，目标如下：3）确定在心血管疾病肌肉和血管重塑过程中调节肢体肌肉脉管系统和骨骼肌纤维相互作用的新因素和信号通路。指导阶段和独立阶段提出的研究结果将显着推进当前对心血管疾病相关肢体病理学的了解。 公共卫生相关性：心血管疾病是美国的主要原因。心血管疾病最未被认识的方面之一是外周动脉疾病（PAD）。这些研究将有助于从机制上理解遗传影响对 PAD 病理学的关键作用，并有助于开发独特的、有针对性的方法来对抗患者群体中的心血管疾病病理学。