NEUROLOGICAL HEREDITARY DEGENERATIVE DISEASES

神经遗传性退行性疾病

• 批准号: 3406800
• 负责人: CHUAN-PU LEE
• 金额: $ 16.55万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 1991-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3406800
• 关键词: Krebs' cycle; NAD(P)H dehydrogenase; NADPH cytochrome c2 reductase; acyl coA dehydrogenases; adenosinetriphosphatase; amyotonia congenita; bioenergetics; biophysics; biopsy; cellular respiration; congenital neuromuscular disorder; cytochrome oxidase; cytochromes; fatty acid metabolism; flavoproteins; human subject; ketoacid; lymphokines; mitochondria; mitochondrial membrane; molecular pathology; muscle disorder chemotherapy; muscle disorders; muscle metabolism; nuclear magnetic resonance spectroscopy; oxidative phosphorylation; phospholipase A2; prednisolone; prednisone; respiratory enzyme; respiratory protein; spectrometry; striated muscles; succinate dehydrogenase; tissue /cell culture

The objective of this proposal is to elucidate the molecular mechanism of the pathogenesis of mitochondrial myopathy and encephalomyopathy. We propose to employ both in vitro and in vivo approaches to identify the metabolic disorders in skeletal muscle of patients and to combine the techniques of biochemistry and biophysics together with clinical investigation. The following approaches will be used: (I). To identify the metabolic disorder(s) in skeletal muscle of patients by evaluating the biochemical and biophysical properties of preparations derived from skeletal muscle biopsies. A. To characterize the isolated mitochondrial preparations with respect to the respiratory and phosphorylating properties, the various partial reactions of the respiratory chain, the ATPase activities, the respiratory chain carrier contents, fatty acid and ketoacid oxidative metabolism and the functional aspects of the mitochondrial membrane; B. to characterize the crude tissue extracts of small biopsy specimens with respect to the respiratory and phosphorylating properties, and various partial reactions of the respiratory chain and those associated with the TCA cycle intermediates; and C. to identify site(s) of structural alterations in biopsy specimens and the preparations derived therefrom by means of ultrastructural examination in parallel with the biochemical studies. (II). To elucidate the molecular mechanism of the therapeutic effects of glucocorticoids in patients. A. To evaluate the in vivo muscle energy metabolism before and after the glucocorticoid treatment by means of 31P-NMR spectroscopy; B. To examine the phospholipase A2 and its inhibitor protein activities in patients' plasma before and after glucocorticoid treatment for possible induction of lipomodulin biosynthesis. C. To elucidate the action of glucocorticoid on mitochondrial metabolism or rats: i. to examine the in vitro effects of glucocorticoids on energy metabolism of isolated mitochondrial preparations of skeletal muscle, liver and heart of rat; and ii. to examine the in vivo effects of glucocorticoids in rats by studying the oxidative metabolism of mitochondrial preparations derived therefrom, and by examing the phospholipase A2 activities of the rat plasma before and after drug treatment. Analysis of the biochemical studies, the 31P-NMR studies and the clinical studies will lend assistance in searching for possible links between the pathological states and the metabolic disorders, in identifying the cause of disease, and ultimately in formulating the proper therapeutic treatments.

该提议的目的是阐明 线粒体肌病和脑病的发病机理。 我们 建议使用体外和体内方法来识别 患者骨骼肌的代谢疾病，并结合 生物化学和生物物理学技术以及临床 调查。 将使用以下方法：（i）。识别 通过评估患者骨骼肌的代谢障碍 制剂的生化和生物物理特性 骨骼肌活检。 答：表征孤立的线粒体 关于呼吸和磷酸化的制剂 性质，呼吸链的各种部分反应， ATPase活动，呼吸链载体内容物，脂肪酸和 酮酸氧化代谢和功能方面 线粒体膜； B.表征的粗组织提取物 相对于呼吸和磷酸化的小型活检标本 呼吸链的特性以及各种部分反应 与TCA循环中间体相关的人；和C.确定 活检标本和制剂的结构改变的位点 通过与超微结构检查得出的超微结构检查 生化研究。 （ii）。阐明 糖皮质激素对患者的治疗作用。 答：评估IN 糖皮质激素治疗前后的体内肌肉能量代谢 通过31p-NMR光谱； B.检查磷脂酶A2和 它在患者血浆之前和之后的抑制剂蛋白活性 糖皮质激素治疗可能诱导脂蛋白 生物合成。 C.阐明糖皮质激素对 线粒体代谢或大鼠：i。检查 糖皮质激素对分离的线粒体制剂的能量代谢 大鼠骨骼肌，肝脏和心脏的骨骼肌肉；和II。检查体内 糖皮质激素在大鼠中的作用通过研究大鼠的作用。 线粒体制剂从中得出，并通过检查 大鼠血浆药物前后的磷脂酶A2活性 治疗。 分析生化研究，31P-NMR研究和 临床研究将为寻找可能的链接提供帮助 在病理状态和代谢性疾病之间，在识别 疾病的原因，最终在制定适当的治疗方面 治疗。