Genetics of Age-Related Cataracts

年龄相关性白内障的遗传学

• 批准号: 7099500
• 负责人: BO CHANG
• 金额: $ 12.3万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099500
• 关键词: aging; cataract; chromosome aberrations; disease /disorder etiology; disease /disorder model; electroretinography; gene expression; genetic polymorphism; genetic strain; genetic susceptibility; immunocytochemistry; laboratory mouse; microarray technology; pathologic process; phenotype; western blottings

Cataracts are the leading cause of blindness in the world, affecting nearly 20.5 million Americans age 40 and older. Most cataracts appear with advancing age; however, the etiology and pathogenesis remain poorly understood. Based on our preliminary studies, age-related cataracts also are very common in mice. At The Jackson Laboratory (TJL), we have just completed a research project to screen aged mice from 35 strains for models of human age-related ocular diseases. This project identified 21 strains of mice with cataracts ranging in age of onset from 8 to 22 months of age. Another 14 strains of mice had clear lenses throughout their lives. Since these 35 strains of mice are all inbred so that the individuals are identical within a strain and all mice are maintained in the same standard environment, these results provide strong evidence that genetic mechanisms contribute to the etiology and pathogenesis of age-related mouse cataracts. The laboratory mouse has become the preeminent model organism for understanding mammalian physiology and genetics for many reasons, including the extensive genetic resources available and the ability to add genes via transgenesis as well as delete them via targeted mutagenesis. This utility has been emphasized with analyses of the human and mouse genome sequences demonstrating that we share over 99% of our genes with mice and that these genes are arranged in a parallel fashion on chromosomes, making it possible to cross-identify genes of interest. Using the mouse as a model, we can focus on the underlying genetic causes by controlling variance due to environmental factors and test environmental factors by altering them in a controlled way. In this research proposal, we will use 21 C57BL/6J-Chr#A chromosome substitution (consomic) strains (mice of the B6 host strain develop age-related cataracts; mice of the A/J donor strain do not) and two parental strains to test the hypothesis that genetic mechanisms contribute to the etiology and pathogenesis of age-related cataracts by phenotyping aged mice of the 21 consomic strains. We will also characterize age-related cataracts in B6 mice and perform genome array analysis of global gene expression differences between lenses with age-related cataracts (B6) and clear lenses (A/J and at least one of the CSS strains in which mice do not develop cataracts).

白内障是世界失明的主要原因，影响了近2050万40岁及40岁以上的美国人。大多数白内障都随着年龄的增长而出现。然而，病因和发病机理仍然很少理解。根据我们的初步研究，与年龄相关的白内障在小鼠中也很常见。在杰克逊实验室（TJL），我们刚刚完成了一项研究项目，以从35种菌株中筛选出年龄的小鼠，用于与人类年龄相关的眼部疾病模型。该项目确定了21种白内障的小鼠菌株 在8到22个月大的发病年龄。另外14株老鼠一生都有清晰的镜头。 由于这35个小鼠菌株都是近交的，因此个体在菌株中相同，并且所有小鼠都保持在相同的标准环境中，因此这些结果提供了有力的证据，表明遗传机制有助于与年龄相关的小鼠白内障的病因和发病机理。由于多种原因，该实验室小鼠已成为理解哺乳动物生理和遗传学的杰出模型生物体，包括可用的广泛遗传资源以及通过转基因添加基因的能力以及通过靶向诱变来删除它们。通过对人类的分析，强调了该效用 小鼠基因组序列表明，我们与小鼠共享99％以上的基因，并且这些基因在染色体上以平行方式排列，从而可以跨识别感兴趣的基因。使用小鼠作为模型，我们可以通过控制环境因素和测试环境因素来通过以受控的方式来控制它们，通过控制差异来关注潜在的遗传原因。在这项研究建议中，我们将使用21 C57BL/6J-CHR＃A染色体取代（辅助）菌株（B6宿主菌株的小鼠会产生与年龄相关的白内障； A/J供体菌株的小鼠没有）和两个父母菌株 检验以下假设，即遗传机制促进了21个辅助菌株的表型老年小鼠的年龄相关性白内障的病因和发病机制。我们还将表征B6小鼠中与年龄相关的白内障，并对与年龄相关性白内障（B6）和透明透镜（A/J和至少一种CSS菌株中的透镜之间的全球基因表达差异进行基因组阵列分析，其中小鼠不发展为无销售）。