Peripheral endothelial and muscle cell pathology in cardiovascular disease

在美国，心血管疾病是主要的死亡原因。外周动脉疾病 (PAD)病理通常被认为是血管性质的，与组织基质有关。 送货。骨骼肌对底物的异常利用很少是调查的目标，但可能 对疾病病理学有同等或更大的贡献。当前的应用程序解决了以下需求 对血管内皮细胞和骨骼肌细胞在免疫应答中的特殊作用的重要理解 心血管疾病缺血/缺氧。该项目的指导阶段的目标是推进 遗传因素对PAD病理影响的机制认识。先前和初步数据 支持这样一种观点，即与Bcl2相关的基因BAG3的多态调节了反应 周围肢体组织对缺血/缺氧的侮辱。我们假设BAG3是一种关键的调节因子 血管内皮细胞和骨骼肌细胞对缺血的反应及BAG3基因的多态性 在这场侮辱中改变它的功能。我们建议从以下具体目标来研究这一专题：1) 确定BAG3在骨骼肌和内皮细胞对低氧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的影响 对缺血/缺氧性损伤的反应。应用程序的此阶段将提供以下方面的培训 肌肉血管生物学将有助于将我的肌肉生物学背景整合到这本书中 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、糖尿病和锻炼。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 从恶病质侮辱中恢复过来。我建议在本主题的独立阶段研究这个主题 3)确定调节相互作用的新因子和信号通路 心血管疾病时肢体肌肉血管和骨骼肌纤维的变化 改建。在指导阶段和独立阶段提出的研究结果将 极大地促进了对心血管疾病相关肢体病理学的当前认识。

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.