Molecular Basis of Hereditary Retinal Degenerations

遗传性视网膜变性的分子基础

• 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
• 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

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.

摘要 本申请中提出的研究的目的是增进我们对 视网膜变性(RD)通过识别与隐性RD和 确定潜在的分子机制。据估计，已知基因有助于 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 这些疾病背后的机制。 近亲交配程度高和近亲婚姻的群体最适合 识别与隐性视网膜疾病相关的基因。遗传性的分子基础 来自巴基斯坦、印度和墨西哥的近交系人群中的视网膜疾病一直不太好 学习。初步分析表明，导致RD的新基因参与了 这些种群。 在这一应用中，研究集中在通过以下方法确定隐性RD的新基因 分析来自印度、巴基斯坦、墨西哥和美国的近亲家庭，以及 了解退化的潜在机制。利用外显子组捕获和研究 测序已被证明是有效地识别导致遗传性的基因突变 条件。一组近亲家庭中与隐性RD相关的基因将是 通过分析外显子序列进行鉴定。本申请书中建议的研究将是 开展的具体目标如下：(1)筛查先证者的已知RD突变 通过使用基因分型阵列和/或通过分析外显子组中的变异来识别新的基因，(2) 通过分析病与非病的外显子序列发现与RD相关的基因 家系成员的RD，和(3)了解疾病的机制 通过确定新的RD基因的功能，我们将识别和评估其效果 编码蛋白质上的突变。 这些新的RD基因可能有助于了解RD和 有助于提高我们对先前发现的RD基因的作用的理解 对视网膜的正常功能至关重要的通路。这些研究的结果将有助于 向患者提供特定的诊断和预后，并确定特定的治疗方法 目标是开发治疗方法来减缓这些疾病的进展，推迟它们的发病，或者 给他们治病。