Peripheral endothelial and muscle cell pathology in cardiovascular disease

描述(申请人提供)：心血管疾病是美国主要的死亡原因。外周动脉疾病(PAD)的病理通常被认为是血管性质的，并与组织基质输送有关。骨骼肌对底物的异常利用很少是研究的目标，但可能对疾病病理有同等或更大的贡献。目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关键了解的需要。该项目指导阶段的目标是促进对遗传对PAD病理影响的机制的理解。以往的和初步的数据支持这一观点，即与Bcl2相关的基因BAG3的多态调节周围肢体组织对缺血/缺氧性损伤的反应。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的多态改变了它在这种损伤中的功能。我们建议从以下几个方面研究这一主题：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基因多态性对骨骼肌和内皮细胞对缺血/缺氧损伤反应的影响。申请的这一阶段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一致的研究重点中。我的长期职业目标是成为一名成功的独立科学家，研究血管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，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一主题，目的如下：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血管和骨骼肌纤维相互作用的新因素和信号通路。在指导阶段和独立阶段提出的研究结果将极大地促进目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死亡原因。心血管疾病最不被认识的一个方面是外周动脉疾病(PAD)。这些研究将有助于从机制上理解遗传影响对PAD病理的关键作用，并有助于开发独特的、有重点的方法来对抗患者群体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.