Mitochondriopathy of Chronically Ischemic Muscle

描述(由申请人提供)： 申请目标：该提案描述了一项为期五年的基础科学研究计划，加上密切指导的实验室指导、课程作业和研讨会，将极大地拓宽我的科学教育，并帮助我成为学术医学中心的独立临床医生/科学家。研究：外周动脉疾病(PAD)是系统性动脉粥样硬化的一种表现，在美国大约有840万人受到影响，其中大多数是老年人。目前对PAD患者的治疗选择仅限于血运重建手术(每年100,000)或截肢(每年50,000)，而有效的非手术治疗选择非常少。PAD的表现，包括跛行和坏疽，是受影响组织内能量水平下降的结果。这种能量状态的降低似乎不仅是由于通过病变动脉的血流量减少，也是因为功能失调的线粒体产生的ATP错误。我们早些时候已经证明，在人类和小鼠慢性缺血的骨骼肌中都存在线粒体功能障碍。我们的小鼠后肢缺血模型的初步结果表明，这些缺陷源于电子传输链复合体III和IV活性降低。此外，我们的结果表明线粒体缺陷与氧化应激有关。这项建议的目的是利用我们的小鼠模型进一步描述电子传输链缺陷，并将线粒体缺陷与肌肉功能障碍和氧化损伤联系起来。已识别的缺陷可能为治疗PAD患者，特别是那些患有不可重建疾病的患者提供一个重要的治疗靶点。我们假设慢性骨骼肌缺血与电子传递链复合体III和IV的活性和含量的改变有关，这些缺陷与肌肉收缩功能障碍和氧化应激的证据有关。提出了四个有针对性的具体目标：目标1：确定和量化缺血肌肉线粒体电子传输链复合体I到IV功能的缺陷。目的2：鉴定功能失调的电子传递链复合体中的亚基缺陷。目的3：线粒体功能障碍与肌肉收缩特性之间的关系。目的4：探讨缺血骨骼肌线粒体功能障碍与氧化损伤的关系。

DESCRIPTION (provided by applicant): Application objective: The proposal describes a five-year program of basic science research coupled with closely mentored laboratory guidance, coursework and seminars that will significantly broaden my scientific education and help me become an independent clinician/scientist in an academic medical center. Research: Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis affecting approximately 8.4 million people in the US, most of them elderly. The current treatment options for patients with PAD are limited to revascularization operations (100,000 per year) or amputations (50,000 per year), while effective non-operative treatment options are very few. The manifestations of PAD, including claudication and gangrene, result from decreased energy levels within the affected tissue. This reduced energy state appears to result not only from reduced blood flow through diseased arteries, but also faulty ATP production from dysfunctional mitochondria. We have earlier demonstrated the presence of mitochondrial dysfunction in both human and mouse chronically ischemic skeletal muscle. Preliminary results from our murine model of hindlimb ischemia suggest that the defects originate from decreased activity of electron transport chain complexes III and IV. Furthermore, our results point to an association between the mitochondrial defects and oxidative stress. The goal of this proposal is to utilize our murine model to further delineate the electron transport chain defects and to correlate mitochondrial defects with muscle dysfunction and oxidative damage. The identified defects may provide an important therapeutic target for treating PAD patients, especially those with unreconstructible disease. We hypothesize that chronic skeletal muscle ischemia is associated with alterations in the activity and content of the electron transport chain complexes III and IV, and that these defects correlate with muscle contractile dysfunction and evidence of oxidative stress. Four focused specific aims are proposed: Aim 1: Identify and quantify defects in the function of electron transport chain complexes I through IV in mitochondria from ischemic muscle. Aim 2: Identify the subunit defects in the dysfunctional electron transport chain complexes. Aim 3: Correlate mitochondrial dysfunction with muscle contractile properties. Aim 4: Correlate mitochondrial dysfunction with oxidative damage in the ischemic skeletal muscle.