Project #4- Therapeutic approaches to CoQ10 deficiencies.

项目

• 批准号: 8741708
• 负责人: Catarina M. Quinzii
• 金额: $ 31.4万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8741708
• 关键词: ATP Synthesis Pathway; Acids; Affect; Age; Age-Months; Anabolism; Antioxidants; Apoptosis; Ascorbic Acid; Benzoquinones; Biochemical; Bioenergetics; Biological Availability; Brain; Bypass; Cell Death; Cell Line; Cell membrane; Cells; Cerebellar Ataxia; Clinical; Coenzyme Q10; Data; Defect; Disease; Disease Progression; Dose; Drug Kinetics; Electron Transport Complex III; Electrons; Fibroblasts; Genetic screening method; Growth; Homologous Gene; Human; In Vitro; Lipids; Longevity; Metabolic; Mitochondria; Mitochondrial Encephalomyopathies; Mitochondrial Respiratory Chain Deficiencies; Molecular; Mus; Mutant Strains Mice; Mutation; NADH dehydrogenase (ubiquinone); Onset of illness; Oral; Oral Administration; Organ; Oxidative Stress; Patients; Phenotype; Play; Proteins; Pyrimidine; Pyrimidine Nucleotides; Reactive Oxygen Species; Residual state; Respiration; Respiratory Chain; Role; Severities; Side; Skin; Specificity; Superoxides; Supplementation; Syndrome; Tail; Testing; Therapeutic; Tissues; Ubiquinone; Weaning; Yeasts; analog; base; cell growth; clinical efficacy; cofactor; comparative efficacy; decaprenyl pyrophosphate synthetase; early onset; idebenone; improved; in vitro testing; in vivo; isoprenoid; mouse model; mutant; novel therapeutics; nucleotide metabolism; overexpression; para-Hydroxybenzoic Acids; prevent; respiratory; response; treatment response; ubiquinone 6; ubiquinone 7; ubiquinone 9

Project Summary Coenzyme Q10 (CoQ10) is a lipophillic molecule composed of a benzoquinone ring and a hydrophobic decaprenyl tail. In the mitochondrial respiratory chain, CoQ10 transports electrons from complexes I and II to complex III. It is also an antioxidant, co-factor for pyrimidine biosynthesis, and modulator of apoptosis. Human CoQ10 deficiency is a genetically and clinically heterogeneous disease. Response to therapy is variable. Our studies of cultured fibroblasts from patients carrying mutations in PDSS2, COQ2, ADCK3, and COQ9, have revealed correlations between level of CoQ10 and oxidative stress; <15% and >60% residual CoQ10 are not associated with oxidative stress, whereas 30-50% residual CoQ10 is associated with oxidative stress, mitochondrial hyperpolarization followed by depolarization and cell death. In cell lines with primary CoQ10 deficiency, incubation of CoQ10 deficient fibroblasts for 1 week with 5mM CoQ10 (but not short-tail ubiquinone analogs) improved bioenergetics indicating pharmacokinetic constraints and dose of CoQ10 may limit efficacy in CoQ10 deficient patients. Based on our studies, we hypothesize that: 1) genotypic heterogenity contributes to the phenotypic variability of CoQ10-deficiency; 2) levels of oxidative stress, respiratory chain deficiency, and apoptosis differ depending on the severity CoQ10 deficiency, and 3) CoQ10 and its analogs have variable efficacy in CoQ10 deficiencies. To test these hypotheses, we propose the following two specific aims: Aim 1) To test genetic and pharmacologic therapies for CoQ10 deficiency in vitro by assessing ADCK3 overexpression and analogs of 4- hydroxybenzoic acid, as approaches to rescue endogenous CoQ10 biosynthesis defects; Aim 2) To test therapies in two mouse model of CoQ10 deficiency by comparing efficacies of oral and intratechal administration of CoQ10 and idebenone in preventing or delaying the onset of the disease in the Pdss2 kd/kd and Coq9X/X mutant mice.

项目概要 辅酶Q10（CoQ10）是一种亲脂性分子，由苯醌环和 疏水性十异戊二烯尾部。在线粒体呼吸链中，CoQ10 传输电子 从复合物I和II到复合物III。它也是一种抗氧化剂，嘧啶的辅助因子 生物合成和细胞凋亡调节剂。人类 CoQ10 缺乏症是一种遗传因素 临床异质性疾病。对治疗的反应是可变的。我们的文化研究 来自携带 PDSS2、COQ2、ADCK3 和 COQ9 突变的患者的成纤维细胞 揭示了 CoQ10 水平与氧化应激之间的相关性； <15% 和 >60% 残留 CoQ10 与氧化应激无关，而 30-50% 的残留 CoQ10 则与氧化应激相关 随着氧化应激，线粒体超极化，随后去极化和细胞死亡。 在原发性 CoQ10 缺乏的细胞系中，将 CoQ10 缺乏的成纤维细胞孵育 1 周 含有 5mM CoQ10（但不是短尾泛醌类似物）可改善生物能学，表明 辅酶 Q10 的药代动力学限制和剂量可能会限制辅酶 Q10 缺乏患者的疗效。 根据我们的研究，我们假设：1）基因型异质性有助于 CoQ10 缺乏症的表型变异； 2) 氧化应激、呼吸链水平 缺乏和细胞凋亡根据 CoQ10 缺乏的严重程度而有所不同，3) CoQ10 及其类似物对于 CoQ10 缺乏症的功效各不相同。为了检验这些假设，我们 提出以下两个具体目标： 目标 1) 测试遗传和药物疗法 通过评估 ADCK3 过表达和 4- 类似物体外 CoQ10 缺乏症 羟基苯甲酸，作为挽救内源性 CoQ10 生物合成缺陷的方法；目标2) 通过比较口服和口服药物的疗效来测试两种 CoQ10 缺乏症小鼠模型的治疗方法 技术内施用辅酶 Q10 和艾地苯醌可预防或延迟发作 Pdss2 kd/kd 和 Coq9X/X 突变小鼠的疾病。