ALPHA-CRYSTALLIN FUNCTION IN LENS BIOLOGY

晶状体生物学中的α-晶状体蛋白功能

基本信息

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
项目类别：
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

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

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项目摘要

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％全球盲目。白内障运营使美国医疗保险系统损失约50亿美元流行病学研究表明人白内障的发病机理涉及遗传，环境和其他与疾病相关的危险因素。镜片结晶蛋白占总晶状体蛋白的90％，并在镜头中起关键作用透明度。遗传性白内障占了很大比例的童年失明，其中50％的白内障具有遗传基础。最近的进步已有很多是为了识别编码„，�和 - 晶状体的基因中的点突变和导致遗传性人类白内障在出生时或早年。对这些的功能研究白内障的单基因形式可以提供有关病因的重要信息与年龄有关的白内障。 - 晶状体是两个多肽的聚集在晶状体上皮和纤维细胞中表达。了解疾病的病因遗传性白内障，我们已经产生了表达„的敲击鼠标模型结晶蛋白突变»A-R49C和„ B-R120G与人常染色体显性遗传性白内障，使用基于胚胎干细胞的技术。这些老鼠在早期阶段发展白内障，将成为了解疾病的重要工具过程。具体目标1将检验– A-晶状体突变体引起的假设突变蛋白在表达突变蛋白后不久发展镜头。第二个特定目的检验了相互作用的假设在突变体之间 - 晶状体蛋白，细胞骨架蛋白和粘附分子中破坏了晶状体细胞的正常发育。第三个特定目的将检验以下假设突变体»A-或€b-晶状体破坏正常透镜蛋白稳态导致异常蛋白质降解。将进行生化，细胞生物学和遗传研究。这些研究的结果将为镜片的分子基础提供新的见解开发和白内障形成，并可能促进战略的发展延迟或预防白内障。