Ubiquitin Function In Eye Lens

描述(申请人提供)：视觉是我们最有价值的感觉。白内障，或晶状体混浊，几乎困扰着所有的老年人，手术摘除混浊的晶状体是最常见的手术，占我们医疗保险预算中最大的项目之一。幸运的是，有一种成功的白内障摘除手术。不幸的是，成功的时间是有限的，因为细胞在白内障手术后残留的晶状体囊袋中生长，导致再混浊或“继发性白内障”。寻找延长术后晶状体清晰度的方法是非常必要的，这对延缓白内障的早期形成也有不可估量的益处。为了实现这些目标，了解晶状体中细胞的增殖和分化是如何控制的是至关重要的。白内障的部分原因是产生了异常的基因和蛋白质。泛素蛋白分解途径(UPP)控制着多种基因的表达和多种蛋白质的水平。我们发现，UPP成分的改变会导致晶状体细胞的异常增殖、分化和白内障。我们的发现清楚地表明，一个功能齐全的UPP在调节晶状体的形成，包括细胞的增殖和分化中起着关键的作用。泛素途径有很多成分。识别UPPs的基本成分并阐明其功能将识别特定的分子，如果对其进行控制，其活性可用于调节增殖和分化。这项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因子(UbcH3、7、10)。在实现这些目标的过程中，我们将确定无数新的药物干预靶点，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奇概念。由于有关UPP的许多信息在许多类型的细胞和组织中都是相似的，我们收集的信息将提供对这一途径如何在许多其他类型的细胞和组织中工作的理解。因此，我们的研究还将告知靶点，这些靶点应该为晶状体以外的许多其他组织提供新的治疗方法，在这些组织中，受控增殖是可取的。这包括角膜、小梁网、视网膜和许多癌症。与公共健康相关：视力是我们最有价值的感觉。白内障，或晶状体混浊，几乎困扰着所有的老年人，手术摘除混浊的晶状体是最常见的手术，占我们医疗保险预算中最大的项目之一。不幸的是，由于“继发性白内障”，晶状体置换手术的成功是有限的。我们将确定无数新的药物干预靶点，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.