Mitochondriopathy of Chronically Ischemic Muscle

慢性缺血性肌肉线粒体病

• 批准号: 7367010
• 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/7367010
• 关键词: 4 hydroxynonenal; Academic Medical Centers; Affect; Amputation; Area; Arteries; Atherosclerosis; Basic Science; Bioenergetics; Biological Assay; Blood flow; Caring; Catalytic Domain; Chronic; Complex; Coupled; DNA; Defect; Deoxyguanosine; Development; Disease; Education; Elderly; Electron Transport; Electron Transport Complex III; Evaluation; Fatigue; Foundations; Functional disorder; Future; Gangrene; Gastrocnemius Muscle; Gel; Goals; Hindlimb; Human; Hydroxylation; Image Analysis; Immunofluorescence Immunologic; In Vitro; Individual; Ischemia; Laboratories; Leg; Limb structure; Lipid Peroxidation; Long-Term Effects; Lower Extremity; Magnetic Resonance; Medical; Medical center; Mentors; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle; Muscle Mitochondria; Nebraska; Northern Blotting; Operative Surgical Procedures; Organ; Oxidative Stress; Pain; Pathogenesis; Patients; Peripheral arterial disease; Phosphocreatine; Population; Preparation; Principal Investigator; Procedures; Process; Production; Property; Proteins; Protocols documentation; Rate; Recovery; Research; Research Personnel; Respiration; Rest; Role; Scientist; Skeletal Muscle; Soleus Muscle; Structure; Therapeutic; Tissues; Training; United States; Universities; Walking; Western Blotting; Work; base; chromosome 5q loss; claudication; design; experience; improved; in vivo; innovation; mitochondrial dysfunction; mortality; oxidation; programs; respiratory; response; therapeutic target

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）： 申请目的：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，课程和研讨会，这将大大拓宽我的科学教育，并帮助我成为一个独立的临床医生/科学家在学术医疗中心。 调研：外周动脉疾病（PAD）是全身动脉粥样硬化的一种表现，在美国影响约840万人，其中大多数是老年人。 PAD患者目前的治疗选择仅限于血运重建手术（每年10万例）或截肢（每年5万例），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，是由于受影响组织内的能量水平降低所致。 这种降低的能量状态似乎不仅是由于通过患病动脉的血流减少，而且是由于功能障碍的线粒体产生错误的ATP。 我们先前已经证明了在人类和小鼠慢性缺血骨骼肌中存在线粒体功能障碍。 从我们的小鼠模型后肢缺血的初步结果表明，缺陷源于电子传递链复合物III和IV的活性降低。 此外，我们的研究结果指出线粒体缺陷和氧化应激之间的关联。 该建议的目的是利用我们的小鼠模型，以进一步描绘的电子传递链缺陷，并与肌肉功能障碍和氧化损伤的线粒体缺陷。 这些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。 我们推测，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，这些缺陷与肌肉收缩功能障碍和氧化应激的证据有关。 提出了四个集中的具体目标：目标1：确定和量化的缺陷，在功能的电子传递链复合物I至IV在线粒体缺血肌肉。 目的2：鉴定功能失调的电子传递链复合物中的亚基缺陷。 目的3：将线粒体功能障碍与肌肉收缩特性相关联。 目的4：将缺血骨骼肌线粒体功能障碍与氧化损伤联系起来。