Antioxidant Defense System and Leydig Cell Aging

抗氧化防御系统和间质细胞老化

基本信息

批准号：
7242568
负责人：
HAOLIN CHEN
金额：
$ 7.96万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7242568
关键词：
Acceleration Age Aging Animal Model Animals Antioxidants Attention C57BL/6 Mouse Caloric Restriction Candidate Disease Gene Cell Aging Cells Cellular Membrane Characteristics Cognition Complex Data Electron Transport Enzymes Free Radicals Glutathione Goals Health Sciences Hormones Human Individual Knockout Mice Libido Light Literature Longevity Luteinizing Hormone Membrane Mitochondria Modeling Molecular Mus Osteoporosis Outcome Oxidative Stress Oxygen Pathway interactions Physiological Play Population Production Protein Isoforms Protein Overexpression Proteins Quality of life Rat Strains Rattus Rattus norvegicus Reaction Reactive Oxygen Species Research Risk Rodent Role Science Serum Signal Transduction Smooth Endoplasmic Reticulum Steroid biosynthesis Superoxide Dismutase Superoxides System Testing Testosterone Texas Transgenic Mice Transgenic Organisms Universities Vitamin E age related aged base catalase cell age coping deprivation enzyme mechanism glutathione peroxidase in vivo insight knockout animal leydig interstitial cell male men phospholipid-hydroperoxide glutathione peroxidase prevent reproductive stressor theories tool

项目摘要

DESCRIPTION (provided by applicant): Serum levels of testosterone are reduced as humans and rodents age. Previous studies of the rat have provided correlative evidence suggesting that age-related increases in oxidative stress and/or deficiencies in the antioxidant defense system may be involved in the reduced ability of aged Leydig cells to produce testosterone. Transgenic and knockout animals represent powerful tools by which to relate candidate genes and their protein products to physiologic outcomes, and thus to examine cause-effect relationships. The major goal of the studies that are proposed herein is to utilize this approach to gain the information needed to begin to test cause-effect relationships between free radical production and the steroidogenic function of aging Leydig cells. The first aim of the proposal is to describe parameters of Leydig cell aging in the mouse by testing the hypotheses that, with aging, testosterone production by Leydig cells of C57BL/6 mice is reduced, mitochondrial superoxide production increases, and there are deficits in the ROS scavenging system (SOD, glutathione peroxidase, catalase) of aged cells. The second aim will focus on transgenic mice that overexpress Gpx4 and on Gpx4 knockdown/knockout mice to test the hypothesis that the overexpression of protective proteins results in suppression or delay in age-related steroidogenic decline that is characteristic of aging Leydig cells, and that deficiencies in the antioxidant defense system result in acceleration or exacerbation of the decline. The successful completion of this research will allow the free radical theory of aging to begin to be tested in aging Leydig cells, an exceptionally well defined system. If successful, the results will begin to move analyses of the "free radical theory of aging" from compelling, though correlative, analyses to ascribing cause and effect. Age-related decline in testosterone in men has relevance to important quality of life issues such as increased osteoporosis, reduced cognition and reduced libido in the aging male population. Studying how testosterone decreases, and what might be done to prevent this from occurring, will provide new insights into how Leydig cells cope with stressors that are present (or increase) with aging, shed light on the underlying molecular basis for age-related functional changes in the Leydig cells, and provide clues as to how to prevent or reverse these changes.

描述（由申请人提供）：随着人类和啮齿动物的年龄，睾丸激素的血清水平降低。先前对大鼠的研究提供了相关的证据，表明抗氧化防御系统中与年龄相关的氧化应激和/或缺乏的增加可能与老年leydig细胞产生睾丸激素的能力降低有关。转基因和基因敲除动物代表了将候选基因及其蛋白质产物与生理结局联系起来的强大工具，从而检查了因果关系。本文提出的研究的主要目的是利用这种方法来获取开始测试自由基生产与衰老leydig细胞的类固醇生成功能之间的因果关系所需的信息。 The first aim of the proposal is to describe parameters of Leydig cell aging in the mouse by testing the hypotheses that, with aging, testosterone production by Leydig cells of C57BL/6 mice is reduced, mitochondrial superoxide production increases, and there are deficits in the ROS scavenging system (SOD, glutathione peroxidase, catalase) of aged cells.第二个目的将集中于过表达GPX4和GPX4敲低/基因敲除小鼠的转基因小鼠，以测试以下假设：保护性蛋白质的过表达导致与年龄相关的类固醇生成的抑制或延迟与年龄相关的类固醇生成下降，这是衰老的Leydig细胞的特征，以及在抗氧化辩护系统中的缺陷或替代性的抗氧化剂。这项研究的成功完成将使自由基的衰老理论开始在衰老的Leydig细胞中测试，这是一个非常明确的系统。如果成功，结果将开始将“自由基衰老理论”的分析从引人注目的（尽管相关）转化为归因于因果的分析。男性睾丸激素与年龄相关的下降与重要的生活质量问题有关，例如增加骨质疏松症，认知能力减少和衰老的性欲减少。研究睾丸激素如何减少，以及为防止发生这种情况而做的事情，将为Leydig细胞如何应对存在（或增加）的压力源如何随着衰老，揭示了与年龄相关的Leydig细胞中与年龄相关功能变化的基础分子基础的启示，并为预防或反向这些变化提供线索。