GENETICS OF MACULAR DEGENERATION

黄斑变性的遗传学

• 批准号: 7261200
• 负责人: KANG ZHANG
• 金额: $ 56.18万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-07-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261200
• 关键词: Adolescent; Age related macular degeneration; Aging; Alleles; Antibodies; Atrophic; Bacterial Artificial Chromosomes; Biochemistry; Biological; Blindness; Candidate Disease Gene; Cell Line; Cellular biology; Choroidal Neovascularization; Chromosome Mapping; Clinical; DNA; DNA Sequence Analysis; Development; Disease; Dominant-Negative Mutation; Drug or chemical Tissue Distribution; Drusen; Electroretinography; Eye; Gene Proteins; Gene Targeting; Genes; Genetic; Genetic Models; Haploidy; Haplotypes; Histology; Immunoelectron Microscopy; Immunofluorescence Immunologic; In Situ Hybridization; Knockout Mice; Lead; Light; Macular degeneration; Messenger RNA; Molecular; Molecular Profiling; Mus; Mutate; Mutation; North Carolina; Northern Blotting; Online Mendelian Inheritance In Man; Ophthalmoscopy; Pathogenesis; Patients; Pattern; Phenotype; Physical Map of the Human Genome; Play; Proteins; Resolution; Retina; Retinal; Retinal Degeneration; Reverse Transcriptase Polymerase Chain Reaction; Role; System; Testing; Transgenic Mice; Transgenic Organisms; base; design; insight; loss of function; mRNA Expression; macula; macular dystrophy; novel; novel strategies; physical mapping; protein expression

DESCRIPTION (provided by applicant): The broad objective of this proposal is to identify a disease gene responsible for North Carolina macular dystrophy and to elucidate the underlying molecular mechanisms that lead to macular degeneration. North Carolina macular dystrophy (OMIM #136550) is an autosomal dominant, highly penetrant macular degeneration characterized by variable phenotypes including confluent drusen in the macula, macular atrophy, and choroidal neovascularization. Three specific aims are designed to test the underlying central hypothesis: that the protein product of the gene for North Carolina macular dystrophy, designated as MCDR1, is essential for the normal function of the macula and that the macular degeneration phenotype is associated with mutations in the MCDR1 gene. The three specific aims are: 1) to identify the disease gene for North Carolina Macular Dystrophy, MCDR1; 2) to characterize the mRNA and protein expression profiles and function of MCDR1; 3) to study the biological effect of MCDR1 in a mouse system. It is important to study the genetic basis of North Carolina macular dystrophy, as it causes juvenile macular degeneration with visual loss. Furthermore, North Carolina macular dystrophy shares important clinical features with age-related macular degeneration (AMD). Drusen is a hallmark of AMD and choroidal neovascularization (CNV) is one of the most important complications of AMD. Both of them are present in patients with North Carolina macular dystrophy. Therefore, these observations make North Carolina macular dystrophy a unique genetic model for AMD. Understanding the molecular mechanisms of MCDR1 should lead to novel insights into the pathogenesis of macular degeneration. Elucidation of the function of the MCDR1 gene may increase our understanding of retinal cell biology in general and drusen formation in particular. Finally, this study may provide information for pursuing novel strategies for treatment of macular degeneration.

描述（由申请人提供）：该提案的主要目标是鉴定导致北卡罗来纳州黄斑营养不良的疾病基因，并阐明导致黄斑变性的潜在分子机制。北卡罗来纳州黄斑营养不良 (OMIM #136550) 是一种常染色体显性遗传、高度渗透性黄斑变性，其特征为多种表型，包括黄斑融合性玻璃疣、黄斑萎缩和脉络膜新生血管形成。 设计了三个具体目标来检验潜在的中心假设：北卡罗来纳州黄斑营养不良基因的蛋白质产物（称为 MCDR1）对于黄斑的正常功能至关重要，并且黄斑变性表型与 MCDR1 基因的突变有关。这三个具体目标是：1）鉴定北卡罗来纳州黄斑营养不良的疾病基因MCDR1； 2) 表征MCDR1的mRNA和蛋白表达谱以及功能； 3）研究MCDR1在小鼠系统中的生物学效应。 研究北卡罗来纳州黄斑营养不良的遗传基础非常重要，因为它会导致青少年黄斑变性并导致视力丧失。此外，北卡罗来纳州黄斑营养不良与年龄相关性黄斑变性（AMD）具有重要的临床特征。玻璃疣是 AMD 的标志，脉络膜新生血管 (CNV) 是 AMD 最重要的并发症之一。这两种情况都存在于北卡罗来纳州黄斑营养不良患者中。因此，这些观察结果使北卡罗来纳州黄斑营养不良成为 AMD 的独特遗传模型。了解 MCDR1 的分子机制应该会对黄斑变性的发病机制产生新的见解。阐明 MCDR1 基因的功能可能会增加我们对视网膜细胞生物学，特别是玻璃疣形成的理解。最后，这项研究可能为寻求治疗黄斑变性的新策略提供信息。