Peripheral endothelial and muscle cell pathology in cardiovascular disease

描述（由申请人提供）：心血管疾病是美国的主要死亡原因。外周动脉疾病（PAD）的病理学通常被认为是血管性的，并与组织基质输送相关。骨骼肌的异常底物利用很少作为研究的目标，但可能对疾病病理学有同等或更大的贡献。本申请解决了对内皮和骨骼肌细胞在响应心血管疾病缺血/缺氧中的特定作用的批判性理解的需要。该项目指导阶段的目标是促进遗传对PAD病理学影响的机械理解。先前的和初步的数据支持这样的想法，即Bcl-2相关的athanogene，BAG 3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BAG 3是内皮细胞和骨骼肌细胞对缺血反应的关键调节因子，BAG 3的多态性改变了其在缺血过程中的功能。我们建议在以下具体目标中研究该主题：1）确定BAG 3在骨骼肌和内皮细胞对缺氧损伤的特异性反应中的作用，以及2）确定BAG 3多态性对骨骼肌和内皮细胞功能响应缺血/缺氧损伤的影响。这一阶段的应用程序将提供肌肉血管生物学的培训，这将有助于我的肌肉生物学背景整合到这个协调的研究重点。我的长期职业目标是成为一名成功的独立科学家，研究血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这个主题，目的如下：3）确定心血管疾病肌肉和血管重塑过程中调节肢体肌肉血管和骨骼肌纤维相互作用的新因子和信号通路。在指导和独立阶段提出的研究成果将显着推进目前的心血管疾病相关肢体病理学的知识。 公共卫生相关性：心血管疾病是美国的主要死亡原因。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对PAD病理的关键作用，并有助于开发独特的、有针对性的方法来对抗患者人群中的心血管疾病病理。

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.