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

基本信息

批准号：
7530551
负责人：
JIYANG CAI
金额：
$ 21.05万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
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/7530551
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 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&apos 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 Personal Satisfaction Phase Plasmids Play Predisposition Production Protein Family Public Health Rate 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 polypeptide research study response transcription factor

项目摘要

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）：我们最近的研究发现了一种与年龄相关性黄斑变性（AMD）相关的新型遗传变异。在对已知危险因素（包括补体因子 H、染色体 10q26 上的 LOC387715 基因、年龄、性别）进行调整后，线粒体 DNA (mtDNA) 的 4917G 等位基因与 AMD 独立相关（OR=3.30，95% CI 1.25 - 7.17，p=0.01）和吸烟状况。 4917G 多态性是单倍群 T 线粒体中的常见变异，会导致复合物 I 的 ND2 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发挥重要作用。线粒体基因组的突变和多态性常常导致能量需求高的组织（例如视网膜）的病理病变。视网膜色素上皮 (RPE) 是 AMD 病变的主要部位。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 的发生和进展。我们假设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类胎儿 RPE 细胞进行测试，这些细胞不会随着衰老而对 mtDNA 造成体细胞损伤。具体目标 1 将确定特定线粒体 DNA 多态性是否与培养的胎儿 RPE 细胞中氧化剂诱导的细胞凋亡的易感性增加相关，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异是否影响对诱导 RPE 抗氧化反应的药物的反应。这些研究的结果将支持使用 mtDNA 单倍型作为遗传生物标志物来识别 AMD 风险增加的人群，并可能作为抗氧化剂补充剂或其他增强视网膜抗氧化防御药物的临床治疗结果的预测因子。公共卫生相关性：年龄相关性黄斑变性 (AMD) 是老年人失明的主要原因。最近的研究发现，罹患 AMD 的风险与线粒体基因组中的一种新的遗传变异有关。这种变化的功能后果的表征将是当前提案的重点。