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.

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.