Molecular Genetics of Age Related Macular Degeneration

年龄相关性黄斑变性的分子遗传学

• 批准号: 8486435
• 负责人: EDWIN M STONE
• 金额: $ 52.96万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8486435
• 关键词: 5' Flanking Region; Affect; Age; Age related macular degeneration; Base Pairing; Biological Assay; Biology; Blindness; Calculi; Candidate Disease Gene; Categories; Cells; Choroid; Clinical; Clinical Medicine; Code; DNA; DNA Sequence; Development; Diagnostic Procedure; Diphosphates; Disease; Eye; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; Human; Individual; Lead; Masks; Methods; Molecular; Molecular Genetics; Mutation; Patients; Pattern; Phenotype; Physicians; Principal Investigator; RNA; Reaction; Retina; Retinal; Risk; Specialist; Structure; Tissues; United States; Variant; aged; cohort; design; disease-causing mutation; effective therapy; experience; high risk; insight; novel; promoter; public health relevance; research study

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the most common cause of severe visual loss in the developed world, affecting more than 10 million people in the United States alone. Approximately 1 in 3 people over the age of 75 are affected to some degree. A significant fraction of this disease is genetic. In this study, we will take advantage of the fact that experienced clinicians can reliably recognize patterns of abnormal structure and function that have discoverable causes. We will couple this clinical expertise with advanced molecular and histopathologic methods to identify new AMD genes and to better understand the disease mechanisms of AMD genes that have been previously discovered. In aim 1, we will identify novel AMD loci and locus-specific AMD phenotypes by correlating the genotypes of well-characterized AMD patients and human eye donors with their ophthalmoscopic and/or histopathologic findings. In aim 2, we will identify new AMD-causing genes and new AMD-causing mutations in known AMD genes by using a novel implementation of pyrophosphate DNA sequencing to screen 13 known AMD genes and 37 candidate AMD genes for disease-causing variations. The entire coding sequence and proximal promoter of these genes will be sequenced in 400 AMD patients and 400 aged control individuals using a novel implementation of pyrophosphate sequencing. Variations found to be significantly skewed in patients or controls will be validated by assaying them in a second cohort of 400 AMD patients and 400 controls. In aim 3, we will investigate the pathophysiologic mechanisms of AMD by characterizing retinal and RPE/choroid gene expression in human donor eyes with both high risk and low risk AMD genotypes. Specifically, for each of five different AMD loci, we will analyze the retinal and RPE/choroidal RNA of five human eye donors who are homozygous for the high-risk genotype and compare these results to those obtained from five donors who are homozygous for the low-risk genotype. These studies will provide new insight into the pathophysiologic mechanisms of AMD that will be valuable for the development of more specific diagnostic methods and more effective therapies.

描述（由申请人提供）：与年龄相关的黄斑变性（AMD）是发达国家严重视觉丧失的最常见原因，仅在美国就影响了超过1000万人。大约有75岁以上的3人在一定程度上受到影响。这种疾病的很大一部分是遗传的。在这项研究中，我们将利用经验丰富的临床医生可以可靠地识别出具有可发现原因的异常结构和功能模式的事实。我们将将这种临床专业知识与晚期分子和组织病理学方法相结合，以鉴定新的AMD基因，并更好地了解先前发现的AMD基因的疾病机制。在AIM 1中，我们将通过将特征良好的AMD患者和人眼供体的基因型与其眼镜和/或组织病理学的发现相关联，通过将新颖的AMD基因座和基因座特异性AMD表型鉴定。在AIM 2中，我们将通过使用新型的焦磷酸DNA测序实现来筛选13个已知AMD基因和37个候选AMD基因来确定已知AMD基因的新型基因和新的引起AMD的突变。这些基因的整个编码序列和近端启动子将在400名AMD患者和400名老年对照个体中进行测序，并使用新型的焦磷酸酯测序实现。发现在患者或对照组中发现的变化显着偏斜，将通过在400名AMD患者和400例对照组中测定它们来验证它们。在AIM 3中，我们将通过表征高风险和低风险AMD基因型的人类供体眼中的视网膜和RPE/脉络膜基因表达来研究AMD的病理生理机制。具体而言，对于五个不同的AMD基因座中的每一个，我们将分析五个人类眼供体的视网膜和RPE/脉络膜RNA，这些供体的捐赠者是纯合的高风险基因型，并将这些结果与从低风险基因型纯合子的五个捐助者那里获得的结果进行比较。这些研究将为AMD的病理生理机制提供新的见解，该机制对于开发更具体的诊断方法和更有效的疗法而言是有价值的。

项目成果

Progress toward effective treatments for human photoreceptor degenerations.

• DOI: 10.1016/j.gde.2009.03.006
• 发表时间: 2009-06
• 期刊: Current opinion in genetics & development
• 影响因子: 4
• 作者: Stone EM

Wide-field spectral-domain optical coherence tomography in patients and carriers of X-linked retinoschisis.

• DOI: 10.1016/j.ophtha.2012.07.051
• 发表时间: 2013-01
• 期刊: Ophthalmology
• 影响因子: 13.7
• 作者: Gregori NZ;Lam BL;Gregori G;Ranganathan S;Stone EM;Morante A;Abukhalil F;Aroucha PR
• 通讯作者: Aroucha PR

Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration.

• DOI: 10.1056/nejmct1000495
• 发表时间: 2010-10-21
• 期刊: NEW ENGLAND JOURNAL OF MEDICINE
• 影响因子: 158.5
• 作者: Folk, James C.;Stone, Edwin M.
• 通讯作者: Stone, Edwin M.

Complement factor H polymorphism p.Tyr402His and cuticular Drusen.

• DOI: 10.1001/archopht.125.1.93
• 发表时间: 2007
• 期刊: Archives of ophthalmology
• 作者: M. Grassi;J. Folk;T. Scheetz;C. M. Taylor;V. Sheffield;E. Stone