The Role of Skeletal Muscle Mitochondria in Peripheral Arterial Disease

骨骼肌线粒体在外周动脉疾病中的作用

• 批准号: 9269073
• 负责人: Terence E Ryan
• 金额: $ 4.11万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269073
• 关键词: Acute; Age; Attenuated; Award; Biochemistry; Biology; Blood Vessels; Blood flow; Brain Hypoxia-Ischemia; Cardiovascular system; Cells; Chromosomes, Human, Pair 7; Clinical; Comorbidity; Data; Development; Diabetes Mellitus; Diagnosis; Electron Transport; Fatty acid glycerol esters; Foundations; Genes; Genetic; Genetic Predisposition to Disease; Goals; Graduate Education; Hindlimb; Human; In Vitro; Inbred BALB C Mice; Inbred Strain; Inbred Strains Mice; Incidence; Intermittent Claudication; Ischemia; Isolated limb perfusion; Limb structure; Link; Mediating; Mitochondria; Modeling; Molecular and Cellular Biology; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Mitochondria; Mutant Strains Mice; Myopathy; Natural regeneration; Nature; Necrosis; Pain; Pathologic; Pathology; Patients; Peptides; Perfusion; Peripheral arterial disease; Pharmacology; Physiological; Predisposition; Prevalence; Process; Property; Quantitative Trait Loci; Respiration; Respiratory physiology; Rest; Role; Series; Skeletal Muscle; Solid; Stenosis; Striated Muscles; Symptoms; System; Techniques; Testing; Tissues; Training; United States; Viral; base; complex IV; cytochrome c oxidase; density; effective therapy; experimental study; feeding; gene therapy; genetic strain; improved; improved functioning; in vivo; knock-down; loss of function; mortality; mouse model; muscle necrosis; muscle physiology; neovascularization; novel; novel therapeutic intervention; physical inactivity; post-doctoral training; public health relevance; response; restoration; success; therapeutic target; therapy development; vessel regression

 DESCRIPTION (provided by applicant): Peripheral artery disease (PAD) is estimated to effect more than 200 million people worldwide. Peripheral artery disease (PAD) presents as either intermittent claudication (IC, pain with activity) or critical limb ischemia (CLI, constant rest pan with a high incidence of necrotic tissue loss). A common misconception is that CLI represents the nature progression of IC. In fact, patients with the same degree of stenosis can present with intermittent claudication, CLI, or can be symptom-free, suggesting that factors other than limb perfusion regulate CLI pathology. Current treatment approaches for PAD/CLI are focused on re-establishing blood flow to the ischemic tissue, implying that blood flow is the decisive factor tha determines whether or not the tissue survives. This project seeks to challenge this clinical paradigm. The discovery that inherent genetic and cell specific properties regulate the cellular response to ischemia/hypoxia, and thus determining the overall degree of tissue damage was initially a surprise because treatments have been aimed solely at recovering of blood flow. Mouse models of peripheral artery disease (PAD) in genetically protected (C57BL/6) and susceptible (BALB/c) inbred strains result in tissue necrosis and muscle myopathies that resemble the pathologies associated with human diagnoses of IC and CLI, respectively. In preliminary studies we discovered that rapid and severe loss of mitochondrial respiratory function is associated with increased muscle myopathy and tissue necrosis in BALB/c mice. Further, we provide evidence supporting that mitochondria are a viable therapeutic target for PAD. Finally, we have identified a genetic target, Cox6a2, which regulates the mitochondrial response to ischemia in skeletal muscle cells through alterations in its expression in response to ischemia. Based on these observations, we hypothesize that skeletal muscle mitochondria are critical regulator's of the response to ischemia, and therefore a primary determinant of myofibers regeneration, neovascularization, and tissue necrosis after limb ischemia. To investigate this hypothesis, the Specific Aims of this proposal are: 1) determine whether reduced skeletal muscle mitochondrial respiratory function increases the susceptibility to ischemic myopathy and limb tissue necrosis, 2) determine whether improved mitochondrial respiratory function in skeletal muscle protects against ischemic myopathy and limb tissue necrosis. Complimentary in vitro and in vivo experimental approaches will be used including physiological, pharmacological, and genetic gain- and loss-of-function models.

 描述（由申请人提供）：据估计，外周动脉疾病 (PAD) 影响着全世界 2 亿多人。外周动脉疾病 (PAD) 表现为间歇性跛行（IC，活动时疼痛）或严重肢体缺血（CLI，持续性）。一个常见的误解是CLI代表了IC的自然进展，事实上，患者的狭窄程度相同。可以出现间歇性跛行、CLI，或者可以无症状，这表明除了肢体灌注之外的因素调节 CLI 病理学，目前 PAD/CLI 的治疗方法集中于重建缺血组织的血流，这意味着血流。是决定组织是否存活的决定性因素，该项目旨在挑战这种临床范例，发现固有的遗传和细胞特异性调节细胞对缺血/缺氧的反应，从而决定整体程度。组织损伤的出现最初是令人惊讶的，因为治疗的目的只是恢复基因保护（C57BL/6）和易感（BALB/c）近交品系的外周动脉疾病（PAD）小鼠模型，从而导致组织坏死和死亡。在初步研究中，我们发现线粒体呼吸功能的快速和严重丧失与 BALB/c 中肌肉肌病和组织坏死的增加有关。此外，我们还提供了证据支持线粒体是 PAD 的可行治疗靶点。最后，我们确定了一个基因靶点 Cox6a2，它通过改变线粒体对缺血的表达来调节骨骼肌细胞对缺血的反应。通过这些观察，我们发现骨骼肌线粒体是缺血反应的关键调节因子，因此是肢体术后肌纤维再生、新生血管形成和组织坏死的主要决定因素为了研究这一假设，该提案的具体目标是：1）确定骨骼肌线粒体呼吸功能的降低是否会增加对缺血性肌病和肢体组织坏死的易感性，2）确定骨骼肌线粒体呼吸功能的改善是否可以预防缺血。将使用补充的体外和体内实验方法，包括生理、药理学和遗传功能获得和丧失模型。