Ubiquitin Function In Eye Lens

眼晶状体中的泛素功能

• 批准号: 8045380
• 负责人: ALLEN TAYLOR
• 金额: $ 44.89万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045380
• 关键词: Accounting; Affect; Animals; Binding; Biochemical; Biological Assay; Boxing; Budgets; Cataract; Cataract Extraction; Cell Cycle; Cell Cycle Regulation; Cell Differentiation process; Cell Nucleus; Cell Proliferation; Cells; Charge; Code; Collaborations; Complex; Cornea; Crystalline Lens; Cullin Proteins; Cultured Cells; Data; Dimensions; Drug Delivery Systems; Elderly; Enzymes; Epithelial; Epithelial Cells; Equilibrium; Excision; Eye; Failure; Figs - dietary; G1/S Transition; G2 Phase; G2/M Arrest; G2/M Transition; Gene Proteins; Genes; Glycine; Grant; Health; Histologic; Homeostasis; Human; Immunohistochemistry; Intervention; Investigation; Knowledge; Length; Lens Fiber; Letters; Link; Literature; Lysine; M cell; Malignant Neoplasms; Medicare; Methods; Microphthalmos; Mitosis; Mus; Operative Surgical Procedures; Organelles; Organogenesis; Pathway interactions; Phase; Phase Transition; Phenotype; Physiological; Positioning Attribute; Prevalence; Procedures; Process; Production; Proliferating; Proteins; Proteolysis; Rattus; Regulation; Relative (related person); Research; Retina; Role; S Phase; Schedule; Secondary to; Site; Specificity; System; Testing; Time; Tissues; Trabecular meshwork structure; Trees; Tryptophan; Ubiquitin; Ubiquitin-Activating Enzymes; Ubiquitin-Conjugating Enzymes; Ubiquitination; Variant; Vision; Work; anaphase-promoting complex; cell growth; cell type; combinatorial; design; expectation; fiber cell; genetic regulatory protein; in vivo; information gathering; lens; multicatalytic endopeptidase complex; novel; novel therapeutics; postnatal; promoter; protein degradation; prototype; regenerative; repaired; research study; success; trafficking; transgene expression; ubiquitin ligase

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.

描述（由申请人提供）：视线是我们最有价值的感觉。白内障或镜头的不透明折磨于不透明的镜头的所有老年人和手术提取是最常见的手术，这是我们Medicare预算中最大的终点项目之一。幸运的是，有一个成功的手术可以清除白内障。不幸的是，成功的持续时间有限，因为细胞在白内障手术后仍保留的镜头囊袋生长，导致重新附加或“继发性白内障”。发现延长手术后镜头清晰度的持续时间的方法至关重要，最初延迟白内障形成也是非常宝贵的好处。要实现这些目标，必须了解细胞增殖和分化如何在镜头中控制。白内障部分原因是基因和蛋白质异常的产生。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。我们已经表明，UPP成分的改变会导致异常的透镜细胞增殖，分化和白内障。我们的发现清楚地表明了功能齐全的UPP在调节晶状体形成（包括细胞增殖和分化）中的关键作用。泛素途径有许多组件。识别UPP的基本组成部分并阐明其功能将识别特定的分子，如果受控，则可以使用其活性来调节增殖和分化。本文提出的研究将确定泛素本身的功能，以及特定的晶状体细胞增殖和分化的特定控制器（UBCH3、7、10）。在实现这些目标时，我们将确定无数新的药理干预目标，以延迟次级白内障的形成。重要的是，我们的每个假设都在测试一个基本的新颖概念。由于在许多类型的细胞和组织中，关于UPP的很多相似之处，我们收集的信息将提供有关该途径在许多其他类型的细胞和组织中如何工作的理解。因此，我们的研究还将告知靶标，这些靶标应该为许多其他组织提供新的治疗剂，除了可以控制的增殖。这包括角膜，小梁网，视网膜和许多癌症。公共卫生相关性：视线是我们最有价值的意义。白内障或镜头的不透明折磨于不透明的镜头的所有老年人和手术提取是最常见的手术，这是我们Medicare预算中最大的终点项目之一。不幸的是，由于“继发性白内障”，透镜替代手术的成功持续时间有限。我们将确定无数新的药理干预措施，以延迟次级白内障的形成。