Proteasome function in the aging retina

蛋白酶体在老化视网膜中的功能

• 批准号: 7117222
• 负责人: Deborah Ann Ferrington
• 金额: $ 35.69万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117222
• 关键词: aging; apoptosis; biochemistry; enzyme activity; enzyme complex; genetically modified animals; laboratory mouse; laboratory rat; major histocompatibility complex; polymerase chain reaction; posttranslational modifications; proteasome; proteolysis; proteomics; retina; retinal pigment epithelium; rod cell; terminal nick end labeling

DESCRIPTION (provided by applicant): The proposed work focuses on the proteasome. This enzyme complex is responsible for most cell protein degradation, including fundamental processes responsible for cell viability and function. We will ask if age-related defects in proteasome function disrupt the function of the retinal pigment epithelium (RPE), and what are the consequences of reduced proteasome function. One focus will be on defining the role of the proteasome in the RPE, where two roles are considered. Since proteasome controls processes that are essential for cell survival, a loss of proteasome function could cause RPE cell death through the accumulation of dysfunctional proteins or the disruption of critical cell pathways. Alternatively, if proteasome participates in the degradation of phagocytosed rod outer segments (ROS), decreased proteasome function could contribute to diminished processing of ROS proteins. A second focus will be to elucidate the biochemical mechanism responsible for the age-dependent loss in proteasome function. The following Aims will be pursued: (1) Define the proteolytic capabilities of the proteasome in the RPE. (a) Define the role of the proteasome in the degradation of phagocytosed rod outer segments. (b) Determine the effect of stressors on RPE proteasome function. (2) Determine age-related changes in retinal proteasome function. (a) Quantify age-related alterations in proteasome function and expression. (b) Identify post-translational modifications in proteasomal subunits. Our investigative approach will include a range of techniques in biochemistry, cell biology, immunology, molecular biology, and proteomics using rodent models of aging, transgenic mice, and cultured cells. Little information is known about proteasome function in the retina, so these studies will provide an important contribution to basic retinal physiology and the effects of aging.

描述（由申请人提供）：拟议的工作着重于蛋白酶体。该酶复合物负责大多数细胞蛋白降解，包括负责细胞活力和功能的基本过程。我们将询问蛋白酶体功能中与年龄相关的缺陷是否破坏视网膜色素上皮（RPE）的功能，以及降低蛋白酶体功能的后果是什么。一个重点是定义蛋白酶体在RPE中的作用，其中考虑了两个角色。由于蛋白酶体控制对细胞存活至关重要的过程，因此蛋白酶体功能的损失可能会通过功能障碍蛋白的积累或临界细胞途径的破坏而导致RPE细胞死亡。或者，如果蛋白酶体参与吞噬棒外部段（ROS）的降解，则蛋白酶体功能降低可能有助于减少ROS蛋白的加工。第二个重点是阐明负责蛋白酶体功能年龄依赖性损失的生化机制。将追求以下目标：（1）定义RPE中蛋白酶体的蛋白水解能力。 （a）定义蛋白酶体在吞噬杆外部段降解中的作用。 （b）确定应激源对RPE蛋白酶体功能的影响。 （2）确定与年龄相关的视网膜蛋白酶体功能的变化。 （a）定量蛋白酶体功能和表达的年龄相关变化。 （b）确定蛋白酶体亚基中的翻译后修饰。我们的研究方法将包括使用衰老，转基因小鼠和培养细胞的啮齿动物模型，包括生物化学，细胞生物学，免疫学，分子生物学和蛋白质组学的一系列技术。关于视网膜中蛋白酶体功能的信息很少，因此这些研究将为基本视网膜生理和衰老的影响提供重要贡献。