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）：我们最近的研究确定了与年龄相关的黄斑变性（AMD）相关的新遗传变异。在调整已知危险因素H，包括loc3877715基因的已知危险因素H上的已知危险因素H染色体10Q26，年龄，年龄，性别，性别，性别和吸烟状态之后，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）。 4917g多态性是单倍型T线粒体的常见变化，在复杂的I.线粒体的ND2亚基中导致非传统变化，天冬氨酸的天冬酸酯。线粒体在控制细胞能量的产生，凋亡，凋亡和氧化还原稳态方面起着至关重要的作用。线粒体基因组的突变和多态性通常会导致能量需求较高的组织（例如视网膜）的病理病变。视网膜色素上皮（RPE）是AMD中病变的主要部位。积累的证据表明，氧化应激引起的RPE功能障碍有助于AMD的发展和进展。我们假设线粒体基因组控制RPE氧化损伤的敏感性中的特定多态性。该假设将在以下两个特定目标中使用培养的人类胎儿RPE细胞进行检验，这些细胞不会对随着衰老而看到的mtDNA造成躯体损害。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细胞中氧化剂诱导的凋亡的敏感性增加有关，以及敏感性是否与线粒体遗传变异有关。具体目标2将确定线粒体基因组的变化是否影响对RPE中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，以识别患有AMD风险增加的人，并可能导致预测抗氧化剂补充剂或其他增强视网膜抗氧化剂防御的临床治疗结果。公共卫生相关性：与年龄相关的黄斑变性（AMD）是老年人失明的主要原因。最近的研究表明，发展AMD的风险与线粒体基因组的新遗传变异有关。这种变异的功能后果的表征将是当前建议的重点。