Cataractogenesis, Connexin Mutants and Genetic Modifiers

描述：白内障是世界上导致失明的主要原因。到目前为止，还没有非手术方法来预防或延缓白内障的形成。人们普遍认为，白内障可由晶状体蛋白功能障碍引起，包括连接蛋白和晶体蛋白，原因包括年龄相关的变化、环境风险因素、易患遗传缺陷或疾病，如糖尿病。然而，维持晶状体透明度所需的晶状体内稳态的调节以及白内障形成的早期事件仍然知之甚少。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。我们最近的发现表明，连接蛋白的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，从而导致白内障。Knockin Alpha3连接蛋白可防止连接蛋白或伽马晶体蛋白基因突变引起的白内障。我们假设，1)通过与野生型连接蛋白相互作用，突变的连接蛋白独特地改变缝隙连接通道的通透性，从而扰乱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)敲打蛋白α3连接蛋白恢复了γ-晶体蛋白的稳定性和/或可溶性，从而挽救了致密的核性白内障；3)连接蛋白突变小鼠的白内障的可变性是由先天的遗传修饰物引起的。建议的研究按三个具体目标组织，以评估这些假设。目的1：确定缝隙连接通透性的改变是否影响α8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：确定敲门α3连接蛋白是否通过恢复突变的GammaB晶体蛋白的稳定性和/或溶解性来挽救突变的GammaB晶体蛋白突变小鼠的核性白内障。目的3：确定影响缝隙连接蛋白突变小鼠晶状体表型的遗传修饰物。这些研究将为缝隙连接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.