Ubiquitin Function In Eye Lens

描述（由申请人提供）：视觉是我们最宝贵的感官。白内障或透镜混浊几乎折磨着所有的老年人，手术摘除混浊的透镜是最常见的手术，在我们的医疗保险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去除白内障。不幸的是，这种成功的持续时间有限，因为细胞生长在白内障手术后残留的透镜囊袋中，导致再混浊或“继发性白内障”。“必须找到延长手术后透镜清晰度的方法，这对延迟白内障的形成也有非常宝贵的好处。为了实现这些目标，必须了解细胞增殖和分化是如何在透镜中控制的。白内障部分是由于产生异常的基因和蛋白质。泛素蛋白水解途径（UPP）控制许多基因的表达和许多蛋白质的水平。我们已经证明，UPP组分的改变导致异常的透镜细胞增殖、分化和白内障。我们的研究结果清楚地表明了一个功能齐全的UPP在调节透镜形成，包括细胞增殖和分化的关键作用。泛素途径有许多组成部分。鉴定UPPs的基本组分并阐明其功能将鉴定特定分子，如果对其活性进行控制，则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，以及透镜细胞增殖和分化的特定控制器（UbcH 3，7，10）。在实现这些目标的过程中，我们将确定大量新的药物干预靶点，以延迟继发性白内障的形成。重要的是，我们的每一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是相似的，我们收集的信息将有助于了解该途径如何在许多其他类型的细胞和组织中发挥作用。因此，我们的研究也将告知除了透镜之外的许多其他组织的靶点，这些靶点应该为许多其他组织提供新的治疗方法，其中控制增殖是期望的。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。白内障或透镜混浊几乎折磨着所有的老年人，手术摘除混浊的透镜是最常见的手术，在我们的医疗保险预算中占最大的项目之一。不幸的是，由于“继发性白内障”，透镜置换手术的成功时间有限。“我们将确定无数新的药物干预靶点，以延迟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.