Cataracts, Connexin Mutants and Genetic Modifier(s)

白内障是世界上致盲的主要原因。到目前为止，还没有非手术的方法来预防或延缓白内障的形成。人们普遍认为，白内障可能是由与年龄相关的变化、环境风险因素、易感遗传缺陷或糖尿病等疾病导致的晶状体蛋白功能失调（包括连接蛋白和晶体蛋白）引起的。然而，维持晶状体透明度和白内障发生的早期事件所需的晶状体稳态调节仍然知之甚少。大多数人类遗传性白内障与晶体蛋白和连接蛋白基因的突变有关。我们建议的总体目标是阐明连接蛋白和晶体蛋白如何调节晶状体透明度和白内障的发生。我们研究的长期目标是开发延缓白内障形成的新疗法。我们最近的研究结果表明，连接蛋白点突变与内源性野生型连接蛋白的结合破坏了晶状体纤维细胞的形成，导致白内障。敲入α 3连接蛋白可预防连接蛋白或-晶体蛋白基因突变引起的白内障。我们假设1)突变型连接蛋白通过与野生型连接蛋白相互作用，独特地改变间隙连接通道的通透性，从而破坏晶状体初级或次级纤维细胞的形成，最终导致不同类型的白内障；2)敲入α 3连接蛋白恢复γ -晶体蛋白的稳定性和/或溶解度，以挽救致密核性白内障；3)连接蛋白突变小鼠白内障的变异性是由易感基因修饰引起的。拟议的研究分为三个具体目的来评估这些假设。目的1：确定间隙连接通透性的改变是否影响alpha8连接蛋白突变小鼠晶状体初级或次级纤维细胞的形成。目的2：确定敲入α 3连接蛋白是否通过恢复突变γ -晶体蛋白的稳定性和/或溶解度来拯救γ -晶体蛋白突变小鼠的核性白内障。目的3：鉴定影响连接蛋白突变小鼠晶状体表型的遗传修饰因子。这些研究将为间隙连接通讯在白内障形成和预防中的作用提供新的机制见解。

DESCRIPTION: Cataracts are the leading cause of blindness in the world. To date, there are no non-surgical methods to prevent or delay cataract formation. It is generally accepted that cataracts can be caused by dysfunctional lens proteins, including connexins and crystallins, resulting from age-related changes, environmental risk factors, predisposed genetic defects or diseases, such as diabetes. However, the regulation of lens homeostasis required for the maintenance of lens transparency and the early events of cataractogenesis remain poorly understood. The majority of human hereditary cataracts are linked to mutations of crystallin and connexin genes. The overall objective of our proposal is to elucidate how connexins and crystallins regulate lens transparency and cataractogenesis. The long-term goal of our research is to develop novel therapeutics for delaying cataract formation. Our recent findings show that the combination of connexin point mutations with endogenous wild type connexins disrupts lens fiber cell formation to cause cataracts. Knockin alpha3 connexin prevents cataracts caused by connexin or gamma-crystallin gene mutations. We hypothesize that 1) by interacting with wild type connexins, mutant connexins uniquely alter gap junction channel permeability to disrupt lens primary or secondary fiber cell formation, ultimately leading to different types of cataracts; 2) knockin alpha3 connexin restores the stability and/or solubility of gamma-crystallin proteins to rescue dense nuclear cataracts; 3) the variability of cataracts in connexin mutant mice is caused by predisposed genetic modifiers. Proposed studies are organized in three specific aims for evaluating these hypotheses. Aim 1: Determine if changes in gap junction permeability affect the formation of lens primary or secondary fiber cells in alpha8 connexin mutant mice. Aim 2: Determine if knockin alpha3 connexin rescues nuclear cataracts in gammaB-crystallin mutant mice by restoring the stability and/or solubility of mutant gammaB-crystallin proteins. Aim 3: Identify genetic modifiers that influence lens phenotypes in connexin mutant mice. These studies will shed new mechanistic insights on the roles of gap junction communication in cataract formation and prevention.