Molecular Basis of Hereditary Retinal Degenerations

遗传性视网膜变性的分子基础

基本信息

批准号：
8730659
负责人：
Radha Ayyagari
金额：
$ 60.07万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-06-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8730659
关键词：
Accounting Affect Aging Biology Blindness Caring Cells Computing Methodologies Critical Pathways Degenerative Disorder Development Diagnosis Disease Disease Association Etiology Evaluation Eye Family Family member Frequencies Functional disorder Gene Mutation Genes Genetic Genotype Goals Inbreeding India Inherited Knock-in Mouse Knockout Mice Knowledge Marriage Mexico Molecular Molecular Profiling Mutation Nucleotides Outcome Study Pakistan Pathogenicity Pathology Patients Pattern Population Process Proteins RNA Recessive Genes Retina Retinal Retinal Degeneration Retinal Diseases Retinal Dystrophy Role Testing Therapeutic Tissues Transcript United States Variant Zebrafish abstracting base cohort disease phenotype early onset exome exome sequencing gene function gene interaction genetic analysis genetic pedigree improved insertion/deletion mutation member molecular pathology mouse model novel outcome forecast proband screening segregation stable cell line therapeutic target therapy design therapy development

项目摘要

Abstract The goal of the studies proposed in this application is to enhance our understanding of retinal degeneration (RD) by identifying additional genes associated with recessive RD and determining the underlying molecular mechanisms. Known genes are estimated to contribute to approximately 30% of cases of recessive RD. The studies proposed here will test the hypothesis that identification of remaining genes for RD will assist in understanding the mechanisms underlying these diseases. Populations with high inbreeding and consanguineous marriages are best suited for identifying genes associated with recessive retinal conditions. The molecular basis of hereditary retinal diseases in inbred populations from Pakistan, India, and Mexico has not been well studied. Preliminary analyses have indicated the involvement of new genes in causing RD in these populations. In this application, studies are focused on identifying new genes for recessive RD by analyzing consanguineous families from India, Pakistan, Mexico, and the United States and understanding the mechanisms underlying degeneration. Studies using exome capture and sequencing have been proven to be efficient in identifying gene mutations causing hereditary conditions. Genes associated with recessive RD in a cohort of consanguineous families will be identified by analyzing the exome sequence. The studies proposed in this application will be carried out with the following specific aims: (1) to screen probands for mutations in known RD genes by using genotyping arrays and/or by analyzing variants in the exome, (2) to identify new genes involved in causing RD by analyzing the exome sequence of affected and unaffected members of pedigrees with RD, and (3) to understand the mechanisms underlying the disease process by determining the function of novel RD genes we will identify and evaluating the effect of mutations on the encoded protein. These new RD genes may assist in understanding the molecular pathology of RD and help in improving our understanding of the role of previously identified RD genes and the pathways critical for normal function of the retina. The outcome of these studies will assist in providing specific diagnoses and prognoses to patients and in identifying specific therapeutic targets to develop therapies to slow the progression of these conditions, delay their onset, or treat them.

抽象的本应用中提出的研究的目的是增强我们对视网膜变性（RD）通过识别与隐性RD相关的其他基因确定潜在的分子机制。估计已知基因有助于大约30％的隐性RD病例。这里提出的研究将测试假设鉴定RD的其余基因将有助于理解这些疾病的基础机制。高近亲和亲密婚姻的人口最适合识别与隐性视网膜条件相关的基因。遗传的分子基础来自巴基斯坦，印度和墨西哥近交的视网膜疾病还不顺利研究。初步分析表明，新基因参与引起RD 这些人群。在此应用中，研究的重点是确定隐性rd的新基因分析来自印度，巴基斯坦，墨西哥和美国和美国以及了解造成变性的机制。使用外显子捕获和事实证明，测序在识别引起遗传性的基因突变方面有效状况。与隐性rd相关的基因将是一群亲属家庭的基因通过分析外显子组序列确定。本应用中提出的研究将是以以下特定目的进行：（1）筛选已知RD突变的概率通过使用基因分型阵列和/或分析外显子中的变体，（2）来识别基因，以识别新的通过分析受影响和不受影响的外显子组序列，涉及引起RD的基因带有RD的血统成员，以及（3）了解该疾病的基础机制通过确定新RD基因的功能，我们将识别和评估效果编码蛋白上的突变。这些新的RD基因可能有助于理解RD的分子病理学帮助我们改善我们对先前鉴定的RD基因和该作用的理解视网膜正常功能至关重要的途径。这些研究的结果将有助于为患者提供特定的诊断和预后，并确定特定的治疗性靶向开发疗法以减缓这些疾病进展，延迟其发作或对待他们。