CALCIUM ACTIVATED PROTEASE IN CATARACT FORMATION

该基金的重点是提供一个详细的机制，控制钙激活蛋白酶家族的钙激活蛋白酶在透镜。 这一点很重要，因为我们实验室的研究证实，过量的钙蛋白酶活性是导致各种啮齿动物白内障的基本潜在机制，并且在几种动物的老化晶状体中发现了钙蛋白酶切割位点。 然而，有两个主要问题需要解决：1）钙蛋白酶在人类透镜中的作用是什么？ 2）新发现的晶状体特异性钙蛋白酶与先前表征的透镜蛋白酶m-钙蛋白酶的功能和关系是什么？ 为了回答这些问题，将追求以下具体目标：1）确定透镜中晶状体特异性钙蛋白酶（Lp 82）的功能和生化特性及其与先前表征的透镜m-钙蛋白酶的关系。2)确定各种钙蛋白酶缺乏对转基因小鼠透镜发育和白内障发生的影响。 3)人透镜中钙蛋白酶的功能测定。这些实验将测试从非人类晶状体获得的关于钙蛋白酶的阳性数据对人类透镜情况的适用性，以及测试新发现的透镜蛋白酶的作用。 希望这些生化数据将导致合理开发基于蛋白酶抑制剂的抗白内障药物。

This grant is focused on providing a detailed mechanism for control of calcium activated proteases of the calpain family in lens. This is important because research from our laboratories established that excess calpain activity is the fundamental underlying mechanism causing a variety of rodent cataracts, and that calpain cleavage sites are found in aging lenses from several types of animals. However, two major questions need to be addressed: 1) What is the role of calpain in human lens? and 2) What is the function and relationship of the newly discovered lens-specific calpains to the previously characterized lens protease m-calpain? In order to answer these questions, these specific aims will be pursued: 1) Determine the function and biochemical properties of lens-specific calpain (Lp82) in lens and its relationship to previously characterized lens m-calpain. 2) Determine the effects of various calpain deficiencies on lens development and cataractogenesis in transgenic mice. 3) Determine the functions of calpains in human lens. These experiments will test the applicability of the positive data on calpain obtained from non-human lenses to the human lens situation, as well as testing the role of a newly discovered lens protease. The hope is that these biochemical data will lead to rational development of anticataract drugs based protease inhibitors.