GENETICS OF MACULAR DEGENERATION

描述(申请人提供)：这项建议的广泛目标是确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症(OMIM#136550)是一种常染色体显性、高穿透性黄斑变性，其特征是各种表型，包括黄斑融合玻璃体、黄斑萎缩和脉络膜新生血管。 设计了三个特定的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产物MCDR1对于黄斑的正常功能是必不可少的，以及黄斑变性表型与MCDR1基因的突变有关。本研究的三个具体目标是：1)确定北卡罗来纳州黄斑营养不良症的致病基因MCDR1；2)鉴定MCDR1的基因和蛋白表达谱及功能；3)研究MCDR1在小鼠系统中的生物学作用。 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)有重要的临床特征。玻璃体形成是AMD的标志，脉络膜新生血管(CNV)是AMD最重要的并发症之一。这两种基因都存在于北卡罗来纳州黄斑营养不良的患者中。因此，这些观察结果使北卡罗来纳州黄斑营养不良成为AMD的独特遗传模式。了解MCDR1的分子机制将有助于对黄斑变性的发病机制有新的认识。阐明MCDR1基因的功能可能会增加我们对视网膜细胞生物学，特别是玻璃体形成的了解。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。

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.