Molecular Basis of Human Visual System Disorders

人类视觉系统疾病的分子基础

基本信息

批准号：
10379316
负责人：
RUI CHEN
金额：
$ 47.95万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379316
关键词：
Affect Algorithms Alleles Amino Acids Animal Model Bioinformatics CRISPR/Cas technology Candidate Disease Gene Code Collection Data Development Diagnosis Disease Electrophysiology (science)Electroretinography European Family Foundations Funding Gene Expression Profile Gene Mutation Generations Genes Genetic Genetic Enhancer Element Genetic Heterogeneity Genetic Transcription Genomics Goals Guanylate Cyclase Histology Human Immunohistochemistry In Vitro Introns Knock-in Mouse Knock-out Knockout Mice Knowledge Messenger RNA Methods Molecular Mutant Strains Mice Mutation Organoids Pathogenicity Pathology Pathway interactions Patient Recruitments Patients Persons Phenotype Photoreceptors Population Proteins Protocols documentation Publications RNA Splicing Recombinant adeno-associated virus (rAAV)Research Project Grants Resources Retina Retinal Defect Retinal Degeneration Retinal Diseases Retinal Dystrophy Retinitis Pigmentosa Sampling Software Tools System Testing Thinness Transmission Electron Microscopy United States Untranslated RNA Variant Virus Visual system structure Work accurate diagnosis clinical heterogeneity cohort data analysis pipeline diagnostic tool disease heterogeneity exome exome sequencing experimental study falls follow-up gene therapy genome sequencing human disease in vivo inherited retinal degeneration insight mouse model multiple data sources mutant mutation screening next generation sequencing novel novel diagnostics postnatal proband programs rare variant recruit response statistics subretinal injection trafficking whole genome

Affect Algorithms Alleles Amino Acids Animal Model Bioinformatics CRISPR/Cas technology Candidate Disease Gene Code Collection Data Development Diagnosis Disease Electrophysiology (science)Electroretinography European Family Foundations Funding Gene Expression Profile Gene Mutation Generations Genes Genetic Genetic Enhancer Element Genetic Heterogeneity Genetic Transcription Genomics Goals Guanylate Cyclase Histology Human Immunohistochemistry In Vitro Introns Knock-in Mouse Knock-out Knockout Mice Knowledge Messenger RNA Methods Molecular Mutant Strains Mice Mutation Organoids Pathogenicity Pathology Pathway interactions Patient Recruitments Patients Persons Phenotype Photoreceptors Population Proteins Protocols documentation Publications RNA Splicing Recombinant adeno-associated virus (rAAV)Research Project Grants Resources Retina Retinal Defect Retinal Degeneration Retinal Diseases Retinal Dystrophy Retinitis Pigmentosa Sampling Software Tools System Testing Thinness Transmission Electron Microscopy United States Untranslated RNA Variant Virus Visual system structure Work accurate diagnosis clinical heterogeneity cohort data analysis pipeline diagnostic tool disease heterogeneity exome exome sequencing experimental study falls follow-up gene therapy genome sequencing human disease in vivo inherited retinal degeneration insight mouse model multiple data sources mutant mutation screening next generation sequencing novel novel diagnostics postnatal proband programs rare variant recruit response statistics subretinal injection trafficking whole genome

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项目摘要

Abstract The goal of this project is to better understand underlying disease mechanisms of Retinitis Pigmentosa (RP), one of the most common forms of inherited retinal degeneration that affects an estimated 100,000 people in the United States alone. To accomplish this, functional studies will be performed for REEP6, a novel RP disease gene that is recently identified. In parallel, additional genes associated with RP will be identified by further characterizing a large cohort of 1,500 RP patients we have recruited during last funding cycle. Through establishing and follow up functional studies of mice model for these newly RP associated disease gene, we expect to gain new insights of disease mechanisms as well as lay the foundation for developing new diagnosis and treatment methods. Mutations in known RP genes account for about 60% of all cases in the European population, suggesting that many additional RP genes remain to be identified. To identify additional RP disease genes, we have collected more than 1,500 patient families from around the world. Screen for mutations in known arRP disease genes suggests that about 600 of these families are likely to carry mutations in novel RP disease genes. Therefore, this collection represents a well characterized, rich resource for identifying new genes that can cause RP. Indeed, whole exome sequencing of a subset of these 600 proband have led the discovery of ten novel disease genes, including the recently identified REEP6 gene. In this proposal, we plan to identify the underlying mutations the remaining proband and newly recruited patients using a combination of whole exome sequencing, bioinformatics, statistics, and functional studies. In parallel, we will conduct functional studies of the newly establish Reep6 knock out and knock in mice to reveal novel interesting underlying disease mechanisms. Our Specific Aims are to: Specific Aim 1. Characterize the mechanism of action of the novel RP disease gene REEP6 Specific Aim 2. Identify and characterize novel RP candidate disease genes Specific Aim 3. Investigate noncoding mutations in RP patients Discovery and characterization of novel RP genes will assist the development of new diagnostic tools and treatments. In addition, since mutations in RP disease genes also cause other retinal dystrophies, functional studies of additional RP disease genes will provide important insights into the molecular mechanisms underlying both RP and retinal dystrophies in general.

抽象的该项目的目的是更好地了解视网膜炎色素炎（RP）的潜在疾病机制，遗传性视网膜变性的最常见形式之一，估计有100,000人仅美国。为此，将对REEP6进行功能研究，这是一种新型的RP 最近发现的疾病基因。同时，与RP相关的其他基因将通过进一步表征了我们在上一个融资周期中招募的1,500名RP患者的大量队列。通过为这些新型RP相关疾病基因建立和跟进小鼠模型的功能研究，我们期望获得有关疾病机制的新见解，并为开发新诊断奠定基础和治疗方法。已知RP基因的突变约占欧洲人口所有病例的60％，这表明许多其他RP基因仍有待鉴定。为了识别其他RP疾病基因，我们收集了来自世界各地的1,500多个患者家庭。筛选已知ARRP疾病基因突变表明，这些家庭中约有600个可能在新型RP疾病基因中携带突变。所以，该集合代表了一种良好的特征，丰富的资源，用于识别可能导致RP的新基因。实际上，这600个概率的一部分的整个外显子组测序导致了十个小说的发现疾病基因，包括最近确定的REEP6基因。在此提案中，我们计划确定潜在的突变使用整个外显子组的组合测序，生物信息学，统计和功能研究。同时，我们将进行功能研究新建立的REEP6在小鼠中敲开并敲门，以揭示新的有趣的潜在疾病机制。我们的具体目的是：特定目的1。表征新型RP疾病基因reep6的作用机理特定目的2。识别和表征新型RP候选疾病基因特定目标3。研究RP患者的非编码突变新型RP基因的发现和表征将有助于开发新的诊断工具和治疗。此外，由于RP疾病基因中的突变也引起其他视网膜营养不良，因此功能性对其他RP疾病基因的研究将为分子机制提供重要的见解一般而言，RP和视网膜营养不良的基础。