Ubiquitin Function In Eye Lens

描述（申请人提供）：视觉是我们最宝贵的感官。白内障或晶状体混浊困扰着几乎所有的老年人，手术摘除混浊晶状体是最常见的手术，在我们的医疗预算中占最大的项目之一。幸运的是，有一种成功的手术可以摘除白内障。不幸的是，成功的持续时间有限，因为白内障手术后残留在晶状体囊袋中的细胞会导致再混浊或“继发性白内障”。发现延长术后晶状体清晰度的方法是非常重要的，而且在初期延缓白内障的形成也是非常有益的。为了实现这些目标，有必要了解细胞增殖和分化是如何在晶状体中被控制的。白内障的部分原因是产生了异常的基因和蛋白质。泛素蛋白水解途径（UPP）控制着许多基因的表达和许多蛋白质的水平。我们已经表明，改变的组成部分的UPP导致异常晶状体细胞增殖，分化和白内障。我们的研究结果清楚地表明，功能齐全的UPP在晶状体形成的调控中起着关键作用，包括细胞增殖和分化。泛素途径有许多组成部分。确定UPPs的基本成分并阐明其功能将确定特定分子，其活性如果受到控制，可用于调节增殖和分化。本文提出的研究将确定泛素本身的功能，以及晶状体细胞增殖和分化的特定控制器（UbcH3, 7, 10）。为了实现这些目标，我们将确定无数新的药物干预目标，以延缓继发性白内障的形成。重要的是，我们的每个假设都在测试一个基本的新概念。由于UPP在许多类型的细胞和组织中都是相似的，我们收集的信息将有助于理解这一途径在许多其他类型的细胞和组织中是如何工作的。因此，我们的研究也将告知靶点，这些靶点应该为许多其他组织提供新的治疗方法，除了晶状体，其中需要控制增殖。这包括角膜、小梁网、视网膜和许多癌症。公共卫生相关性：视觉是我们最宝贵的感官。白内障或晶状体混浊困扰着几乎所有的老年人，手术摘除混浊晶状体是最常见的手术，在我们的医疗预算中占最大的项目之一。不幸的是，由于继发性白内障，晶状体置换手术的成功时间有限。我们将确定无数新的药物干预目标，以延缓继发性白内障的形成。

DESCRIPTION (provided by applicant): Sight is our most valued sense. Cataract, or opacification of the lens afflicts virtually all the elderly and surgical extraction of the opacified lens is the most commonly performed surgery, accounting for among the largest line items in our Medicare budget. Fortunately, there is a successful procedure for removing cataracts. Unfortunately, the success is of limited duration because cells grow in the lens capsular bag that remains after cataract surgery causing re-opacification or "secondary cataract." It is essential to discover means to extend the duration of lens clarity after surgery and it would also be of invaluable benefit to delay cataract formation initially. To accomplish these objectives it is essential to understand how cell proliferation and differentiation are controlled in the lens. Cataract is due in part to production of abnormal genes and proteins. The ubiquitin proteolytic pathway (UPP) controls the expression of many genes and the levels of many proteins. We have shown that alteration of components of the UPP result in abnormal lens cell proliferation, differentiation and cataracts. Our findings clearly demonstrate a critical role for a fully functional UPP in regulation of lens formation, including cell proliferation and differentiation. There are many components to a ubiquitin pathway. Identifying essential components of UPPs and elucidating their function will identify specific molecules, the activity of which, if controlled, can be used to regulate proliferation and differentiation. The research proposed herein will identify functions of ubiquitin per se, and specific controllers (UbcH3, 7, 10) of lens cell proliferation and differentiation. In accomplishing these objectives we will identify a myriad of new targets for pharmacologic intervention to delay formation of secondary cataract. Importantly, each of our hypotheses is testing a fundamental novel concept. Since much about the UPP is similar in many types of cells and tissues, the information we gather will provide understanding of how this pathway works in many other types of cells and tissue. Thus, our research will also inform about targets which should provide new therapeutics for many other tissues, in addition to lens, where controlled proliferation is desirable. This includes cornea, trabecular meshwork, retina and many cancers. PUBLIC HEALTH RELEVANCE: Sight is our most valued sense. Cataract, or opacification of the lens afflicts virtually all the elderly and surgical extraction of the opacified lens is the most commonly performed surgery, accounting for among the largest line items in our Medicare budget. Unfortunately, the success of lens replacement surgery is of limited duration because of "secondary cataract." We will identify a myriad of new targets for pharmacologic intervention to delay formation of secondary cataract.