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.

抽象的本申请中提出的研究的目的是增强我们对通过识别与隐性 RD 相关的其他基因来识别视网膜变性 (RD) 确定潜在的分子机制。已知基因估计有助于大约 30% 的隐性 RD 病例。这里提出的研究将测试假设识别 RD 的剩余基因将有助于理解这些疾病的潜在机制。近亲繁殖和近亲结婚的人群最适合识别与隐性视网膜疾病相关的基因。遗传的分子基础来自巴基斯坦、印度和墨西哥的近交种群的视网膜疾病状况不佳研究过。初步分析表明新基因参与导致 RD 这些人群。在此应用中，研究重点是通过以下方式识别隐性 RD 的新基因：分析来自印度、巴基斯坦、墨西哥和美国的近亲家庭，了解退化的机制。使用外显子组捕获和测序已被证明可以有效识别导致遗传性的基因突变状况。近亲家庭队列中与隐性 RD 相关的基因将被通过分析外显子组序列来鉴定。本申请中提出的研究将是进行的具体目的如下：（1）筛选先证者已知 RD 中的突变通过使用基因分型芯片和/或通过分析外显子组中的变异来识别基因，(2) 识别新的通过分析受影响和未受影响的外显子组序列，找出与引起 RD 相关的基因患有 RD 的家系成员，以及 (3) 了解疾病的潜在机制通过确定新 RD 基因的功能，我们将识别并评估其效果编码蛋白质的突变。这些新的 RD 基因可能有助于理解 RD 的分子病理学和帮助我们更好地理解先前确定的 RD 基因的作用以及对视网膜正常功能至关重要的通路。这些研究的结果将有助于为患者提供具体的诊断和预后并确定具体的治疗方法目标是开发治疗方法来减缓这些疾病的进展、延迟其发作，或对待他们。