ALPHA-CRYSTALLIN FUNCTION IN LENS BIOLOGY

晶状体生物学中的α-晶状体蛋白功能

• 批准号: 8288209
• 负责人: USHA P ANDLEY
• 金额: $ 47.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-05-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288209
• 关键词: A Mouse; Accounting; Address; Adult; Affect; Age; Apoptosis; Area; Biochemical; Biological; Biology; Birth; Blindness; Cataract; Cataract Extraction; Cell Adhesion Molecules; Cell Differentiation process; Cell Nucleus; Cell Survival; Cell physiology; Cells; Cellular Structures; Childhood; Crystalline Lens; Crystallins; Cytoskeletal Proteins; Cytoskeleton; Defect; Development; Disease; E-Cadherin; Embryo; Embryonic Development; Environmental Risk Factor; Epidemiologic Studies; Epithelial; Epithelial Cells; Etiology; Exhibits; Eye Lens Protein; Fiber; Gene Deletion; Gene Mutation; Genes; Genetic; Genetic Transcription; Goals; Growth; Growth and Development function; Health Care Costs; Heat shock proteins; Homeostasis; Human; Inherited; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Lens Fiber; Link; Maintenance; Medicare; Molecular; Molecular Chaperones; Morphology; Mus; Mutation; Optics; Pathogenesis; Pathology; Patients; Phenotype; Play; Point Mutation; Process; Proliferation Marker; Property; Proteins; Proteomics; Research; Risk Factors; Role; Signal Transduction; Signaling Protein; Solubility; Staging; Structure; System; Technology; Testing; Time; Toxic effect; Tubulin; Visual impairment; Water; Work; age related; alpha-Crystallins; base; congenital cataract; cost; early childhood; early onset; embryonic stem cell; fiber cell; in vivo; infancy; insight; lens; lens protein; lens transparency; mouse model; mutant; novel; operation; polypeptide; prevent; protein degradation; tool

Project Summary Cataract formation is the most common cause of vision loss, accounting for 45% of blindness worldwide. Cataract operations cost the US Medicare system ~$5 billion annually. Epidemiological studies show that the pathogenesis of human cataracts involves genetic, environmental, and other disease-associated risk factors. Lens crystallins account for 90% of the total lens proteins and play a key role in lens transparency. Hereditary cataracts account for a significant proportion of childhood blindness, and 50% of these cataracts have a genetic basis. Much recent progress has been made in identifying point mutations in genes that encode ¿, ¿ and ¿-crystallins and lead to hereditary human cataracts at birth or an early age. Functional studies on these monogenic forms of cataract could provide important information about the etiology of age-related cataracts. ¿-crystallin is an aggregate of two polypeptides ¿A and ¿B which are expressed in lens epithelial and fiber cells. To understand disease etiology in hereditary cataracts, we have generated knock-in mouse models expressing the ¿- crystallin mutations ¿A-R49C and ¿B-R120G linked with human autosomal dominant hereditary cataracts, using embryonic stem cell-based technologies. These mice develop cataracts at an early stage and will be an important tool to understand disease process. Specific Aim 1 will test the hypothesis that the ¿A-crystallin mutant causes epithelial and fiber cell disruption soon after the mutant protein is expressed in the developing lens. The second Specific Aim tests the hypothesis that the interaction between mutant ¿-crystallin, cytoskeletal proteins and adhesion molecules disrupts the normal development of the lens cells. The third Specific Aim will test the hypothesis that mutant ¿A- or ¿B-crystallin disrupt normal lens protein homeostasis leading to abnormal protein degradation. Biochemical, cell biological and genetic studies will be performed. The results of these studies will provide new insights into molecular basis of lens development and cataract formation, and may promote the development of strategies to delay or prevent cataracts.

项目摘要 白内障形成是视力丧失的最常见原因，占45%， 全世界失明白内障手术花费了美国医疗保险系统约50亿美元 每年。流行病学研究表明，人类白内障的发病机制 涉及遗传、环境和其他疾病相关的风险因素。透镜 晶体蛋白占透镜总蛋白的90%，在透镜中起着关键作用 透明度遗传性白内障在儿童期占很大比例 失明，其中50%的白内障有遗传基础。最近的许多进展 在鉴定编码晶体蛋白的基因中的点突变方面取得了进展， 导致人类先天性白内障。功能研究， 单基因形式的白内障可以提供关于白内障病因的重要信息， 老年性白内障晶体蛋白是两种多肽A和B的聚集体， 在透镜上皮细胞和纤维细胞中表达。了解疾病的病因， 遗传性白内障，我们已经产生了基因敲入小鼠模型，表达了 晶状体蛋白突变<$A-R49 C和<$B-R120 G与人类常染色体显性遗传相关 遗传性白内障，使用胚胎干细胞技术。这些小鼠 在早期发展白内障，将是了解疾病的重要工具 过程具体目标1将检验以下假设：A-晶状体蛋白突变体导致 上皮和纤维细胞破裂后不久，突变蛋白表达在 显影透镜。第二个具体目标测试的假设是， 突变晶体蛋白，细胞骨架蛋白和粘附分子之间的相互作用， 透镜细胞的正常发育。第三个具体目标将检验以下假设： 突变型透镜蛋白A-或B-晶状体蛋白破坏正常晶状体蛋白稳态，导致异常 蛋白质降解将进行生物化学、细胞生物学和遗传学研究。 这些研究结果将为透镜的分子基础提供新的认识 发展和白内障的形成，并可能促进战略的发展， 延缓或预防白内障。