GENETIC DETERMINANTS OF CATARACT

描述(申请人提供)：晶状体在脊椎动物的前眼发育和屈光视觉中起着核心作用。晶状体透明度丧失或白内障(S)是导致低视力的临床重要原因，尽管手术治疗，但仍是全球范围内导致失明的主要原因(约40%)。通常，白内障是随着年龄的增长(40岁)而获得的，是一种多因素或复杂的疾病，涉及环境和遗传风险因素。此外，白内障可能是一种孟德尔遗传性疾病，通常以青少年发病为主，已经描述了许多人类白内障的小鼠模型。虽然已经确定了几个与年龄相关的白内障的环境风险因素，但人们对遗传因素的性质和确切作用知之甚少，据估计，遗传因素约占风险的50%。然而，越来越多的证据表明，遗传性白内障的基因也与年龄相关的白内障有关。这项研究的总体目标是促进对导致白内障的分子机制/途径的了解。具体地说，我们建议识别人类遗传性白内障的新基因，并使用分子遗传学和基因组技术相结合的方法在人类老年性白内障的小鼠模型中识别致病基因。这些研究结果将为晶状体发育、衰老和白内障发生的分子基础提供新的见解，并最终可能有助于发现延迟、逆转甚至预防白内障形成的非手术方法。 公共卫生相关性：年龄相关性白内障困扰着美国40岁以上人口中的2000多万(约17%)，尽管手术治疗的直接医疗费用增加，但仍是导致低视力的主要原因。先天性和婴儿型白内障也是儿童视力受损的重要原因，儿童白内障的手术治疗容易发生术后并发症，包括后囊混浊、无晶状体青光眼或高眼压、眼球运动障碍(眼球震颤、斜视、弱视)、葡萄膜炎和视网膜脱离。本研究旨在促进对导致白内障的分子遗传学机制的了解，并有助于发现替代的非手术治疗白内障的方法。

DESCRIPTION (provided by applicant): The crystalline lens plays a central role in vertebrate anterior eye development and refractive vision. Loss of lens transparency, or cataract(s), is a clinically important cause of low vision that despite surgical treatment remains a leading cause (~40%) of blindness worldwide. Typically, cataract is acquired with aging (>40 yrs) as a multi-factorial or complex disorder involving environmental and genetic risk factors. In addition, cataract may be inherited as a Mendelian disorder usually with juvenile-onset, and many mouse models of human cataract have been described. While several environmental risk factors have been established for age-related cataract, little is known about the nature and precise role of genetic factors that are estimated to account for ~50% of the risk. However, there is increasing evidence that genes underlying inherited forms of cataract are also involved in age-related cataract. The overall goal of this research is to advance understanding of the molecular mechanisms/pathways that lead to cataract. Specifically, we propose to identify novel genes for inherited forms of cataract in humans, and to identify the causative gene in a mouse model of human age-related cataract using a combination of molecular genetic and genomic techniques. Results from these studies will provide new insights about the molecular basis of lens development, aging and cataractogenesis, and ultimately may contribute to the discovery of non-surgical means to delay, reverse or even prevent cataract formation. PUBLIC HEALTH RELEVANCE: Age-related cataract afflicts more than 20 million of the US population over age 40 (~17%), and despite increasing direct medical costs for surgical treatment, is the leading cause of low vision. Congenital and infantile forms of cataract are also a significant cause of visual impairment in childhood, and surgical management of pediatric cataract is susceptible to post-operative complications including, posterior capsular opacification, aphakic glaucoma or ocular hypertension, eye movement disorders (nystagmus, strabismus, amblyopia), uveitis and retinal detachment. This research aims to advance understanding of the molecular genetic mechanisms that cause cataract, and contribute to the discovery of alternative non-surgical treatments for cataract.