Cataracts, Connexin Mutants and Genetic Modifier(s)

白内障、连接蛋白突变体和基因修饰剂

• 批准号: 7211851
• 负责人: Xiaohua Gong
• 金额: $ 38万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211851
• 关键词: Affect; Age; Alleles; American; Biochemical; Blindness; Candidate Disease Gene; Cataract; Cells; Chromosomes; Chromosomes, Human, Pair 2; Communication; Connexins; Consomic Mouse Strain; Crystallins; Data; Diabetes Mellitus; Disease; Environmental Risk Factor; Event; Fiber; Gap Junctions; Gene Mutation; Genes; Genetic; Goals; Homeostasis; Human; Inherited; Knock-out; Lens Fiber; Light; Link; Maintenance; Maps; Methods; Mus; Mutant Strains Mice; Mutation; Nuclear; Operative Surgical Procedures; Permeability; Phenotype; Physiological; Point Mutation; Prevention; Property; Proteins; Regulation; Research; Role; Severities; Solubility; System; Xenopus oocyte; age related; base; fiber cell; gamma-Crystallins; gammaB crystallin; gap junction channel; in vivo; insight; lens; lens protein; lens transparency; mutant; novel therapeutics; prevent

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.

描述：白内障是世界上致盲的主要原因。到目前为止，还没有非手术方法来预防或延迟白内障的形成。一般认为，白内障可由功能失调的透镜蛋白引起，包括连接蛋白和晶体蛋白，其由年龄相关的变化、环境风险因素、易患的遗传缺陷或疾病如糖尿病引起。然而，对于维持透镜透明度所需的透镜内稳态的调节和白内障发生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透镜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透镜纤维细胞的形成，从而导致白内障。敲入α 3连接蛋白可预防由连接蛋白或γ-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，突变型连接蛋白独特地改变间隙连接通道的渗透性，从而破坏透镜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-晶状体蛋白的稳定性和/或溶解性，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的遗传修饰剂引起的。拟议的研究组织在三个具体的目标，以评估这些假设。目的1：确定间隙连接通透性的变化是否影响α 8连接蛋白突变小鼠透镜初级或次级纤维细胞的形成。目标二：确定敲入α 3连接蛋白是否通过恢复突变γ B-晶状体蛋白的稳定性和/或溶解性来挽救γ B-晶状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透镜表型的遗传修饰因子。这些研究将为缝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。