Mitochondrial DNA Variations and Susceptibility to Oxidative Injury in the RPE

RPE 中线粒体 DNA 变异和氧化损伤的易感性

• 批准号: 7667245
• 负责人: JIYANG CAI
• 金额: $ 19.19万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667245
• 关键词: 10q26; ATP Synthesis Pathway; Affect; Age; Age related macular degeneration; Aging; Alleles; Antioxidants; Apoptosis; Asparagine; Aspartic Acid; Base Pairing; Binding; Biological Assay; Biological Markers; Blindness; Cell Nucleus; Cells; Chromosomes; Circular DNA; Clinical Treatment; Complement Factor H; Complex; DNA lesion; Data; Defect; Degenerative Disorder; Development; Drug Metabolic Detoxication; Elderly; Electron Transport; Energy Metabolism; Ensure; Enzymes; Etiology; Eye; Functional disorder; Gender; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Haplogroup; Haplotypes; Homeostasis; Hot Spot; Housing; Human; Human Genetics; Individual; Inherited; Injury; Lead; Leber' s Hereditary Optic Neuropathy; Lesion; Light; Link; Lipids; Measures; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Mutation; Nuclear; Nucleic Acids; Outcome; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxygen Consumption; Oxygen measurement, partial pressure, arterial; Phase; Plasmids; Play; Predisposition; Production; Protein Family; Reactive Oxygen Species; Replication-Associated Process; Reporter; Research Personnel; Respiratory Chain; Response Elements; Retina; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal RNA; Risk; Risk Factors; Role; Set protein; Site; Smoking Status; Somatic Mutation; Structure of retinal pigment epithelium; Sulforaphane; Supplementation; Testing; Time; Tissues; Transfection; Transfer RNA; Translations; Variant; Zinc; age related; fetal; gene environment interaction; mitochondrial genome; novel; nuclear factor-erythroid 2; oxidative damage; polypeptide; public health relevance; research study; response; transcription factor

DESCRIPTION (provided by applicant): Our recent studies have identified a novel genetic variation associated with age-related macular degeneration (AMD). The 4917G allele of mitochondrial DNA (mtDNA) was independently associated with AMD (OR=3.30, 95% CI 1.25 - 7.17, p=0.01) following adjustment for known risk factors including complement factor H, LOC387715 gene on chromosome 10q26, age, gender and smoking status. The 4917G polymorphism is a common variation in haplogroup T mitochondria and results in a non-synonomous change, asparagine for aspartic acid, in the ND2 subunit of Complex I. Mitochondria play essential roles in controlling cellular energy production, apoptosis and redox homeostasis. Mutations and polymorphisms of the mitochondrial genome often lead to pathological lesions in tissues with high energy demand, such as the retina. The retinal pigment epithelium (RPE) is a primary site of lesion in AMD. Accumulating evidence indicates that oxidative stress induced dysfunction of the RPE contributes to the development and progression of AMD. We hypothesize that specific polymorphisms in the mitochondrial genome control susceptibility to oxidative injury in the RPE. The hypothesis will be tested in the following two specific aims using cultured human fetal RPE cells which do not carry somatic damage to the mtDNA seen with aging. Specific Aim 1 will determine whether specific mitochondrial DNA polymorphisms are associated with increased susceptibility to oxidant-induced apoptosis in cultured fetal RPE cells and whether the sensitivity is associated with mitochondrial genetic variations. Specific Aim 2 will determine whether variations in the mitochondrial genome affect responses to agents that induce the antioxidant responses in the RPE. Results from these studies will support the use of mtDNA haplotypes as a genetic biomarker in identifying people with increased risk of AMD and may lead to predictors of the outcome of clinical treatment with antioxidant supplementation or other agents that augment the antioxidant defense of the retina. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people. Recent studies have identified that the risk of developing AMD is associated with a novel genetic variation in the mitochondrial genome. Characterization of the functional consequences of such variation will be the focus of the current proposal.

描述（由申请人提供）：我们最近的研究已经确定了一种与年龄相关性黄斑变性（AMD）相关的新的遗传变异。经校正补体因子H、染色体10 q26上的LOC 387715基因、年龄、性别和吸烟状况等已知危险因素后，线粒体DNA（mtDNA）4917 G等位基因与AMD独立相关（OR=3.30，95%CI 1.25 - 7.17，p=0.01）。4917 G多态性是单倍型群T线粒体中的常见变异，并导致复合体I的ND 2亚基中天冬酰胺变为天冬氨酸的非同义变化。线粒体在控制细胞能量产生、细胞凋亡和氧化还原稳态中起重要作用。线粒体基因组的突变和多态性通常导致高能量需求组织（如视网膜）的病理性病变。视网膜色素上皮（RPE）是AMD的主要病变部位。越来越多的证据表明，氧化应激诱导的RPE功能障碍有助于AMD的发生和发展。我们推测线粒体基因组中的特定多态性控制RPE对氧化损伤的易感性。该假设将在以下两个具体目标中使用培养的人胎儿RPE细胞进行测试，这些细胞不携带随衰老而观察到的mtDNA的体细胞损伤。具体目标1将确定特定的线粒体DNA多态性是否与培养的胎儿RPE细胞对氧化剂诱导的细胞凋亡的敏感性增加相关，以及敏感性是否与线粒体遗传变异相关。具体目标2将确定线粒体基因组的变化是否影响对诱导RPE中抗氧化反应的试剂的反应。这些研究的结果将支持使用mtDNA单倍型作为识别AMD风险增加的人的遗传生物标志物，并可能导致抗氧化剂补充剂或其他增强视网膜抗氧化防御的药物的临床治疗结果的预测因子。 公共卫生相关性：视网膜相关性黄斑变性（AMD）是老年人失明的主要原因。最近的研究已经确定，发展AMD的风险与线粒体基因组中的一种新的遗传变异有关。对这种变化的功能后果的描述将是本提案的重点。