Mitochondriopathy of Chronically Ischemic Muscle

慢性缺血性肌肉线粒体病

• 批准号: 6902254
• 负责人: Iraklis Ilias Pipinos
• 金额: $ 13.07万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6902254
• 关键词: active sites; adenosine triphosphate; atherosclerosis; carbonyl compound; deoxyguanosine; disease /disorder model; electron transport; immunofluorescence technique; ischemia; laboratory mouse; leg; lipid peroxides; messenger RNA; mitochondrial disease /disorder; molecular pathology; muscle contraction; northern blottings; oxidative stress; peripheral blood vessel disorder; spectrometry; striated muscles; two dimensional gel electrophoresis; western blottings

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.

描述（由申请人提供）： 申请目标：该提案描述了一个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，这将显着拓宽我的科学教育，并帮助我成为学术医疗中心的独立临床医生/科学家。 研究：外周动脉疾病 (PAD) 是全身动脉粥样硬化的一种表现，影响着美国约 840 万人，其中大多数是老年人。 目前PAD患者的治疗选择仅限于血运重建手术（每年10万例）或截肢术（每年5万例），而有效的非手术治疗选择很少。 PAD 的表现（包括跛行和坏疽）是由受影响组织内的能量水平降低引起的。 这种能量状态的降低似乎不仅是由于患病动脉的血流量减少造成的，也是由于功能失调的线粒体产生了错误的 ATP 所致。 我们之前已经证明人类和小鼠慢性缺血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，缺陷源于电子传递链复合物 III 和 IV 活性的降低。 此外，我们的结果表明线粒体缺陷与氧化应激之间存在关联。 该提案的目标是利用我们的小鼠模型进一步描绘电子传递链缺陷并将线粒体缺陷与肌肉功能障碍和氧化损伤相关联。 所发现的缺陷可能为治疗 PAD 患者，特别是那些患有不可修复疾病的患者提供重要的治疗靶点。 我们假设慢性骨骼肌缺血与电子传递链复合物 III 和 IV 的活性和含量的改变有关，并且这些缺陷与肌肉收缩功能障碍和氧化应激的证据相关。 提出了四个重点具体目标： 目标 1：识别并量化缺血性肌肉线粒体中电子传递链复合物 I 至 IV 的功能缺陷。 目标 2：识别功能失调的电子传递链复合物中的亚基缺陷。 目标 3：将线粒体功能障碍与肌肉收缩特性相关联。 目标 4：将线粒体功能障碍与缺血骨骼肌的氧化损伤联系起来。