Stress, Glucocorticoid and Leydig Cell Aging

压力、糖皮质激素和间质细胞老化

基本信息

批准号：
7495628
负责人：
HUI-BAO GAO
金额：
$ 3.28万
依托单位：
SHANGHAI JIAO TON UNIVERSITY SCH OF MED
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：
2006-09-01 至 2009-08-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7495628
关键词：
11p Acceleration Address Adrenal Glands Age Aging Aging-Related Process Animals Award Biochemistry Biology Biomedical Research Bolus Infusion Brain Cell Aging Cell Nucleus Cellular Structures China Chinese People Chromosomes Chronic Chronic stress Condition Corticosterone Cytosol Daily Data Dendrites Elevation Enzymes Evaluation Event Exposure to Funding Generations Glucocorticoid Receptor Glucocorticoids Hippocampus (Brain)Hour Hydroxysteroid Dehydrogenases Immobilization Immunohistochemistry Learning Length Location Longevity Luteinizing Hormone Male Genital Organs Measures Mediating Medical Metabolism Methods Molecular Biology Nerve Degeneration Neurons Numbers Organ Oxidative Stress Paper Pattern Peer Review Performance Physiological Principal Investigator Process Production Publishing RU-486 Rate Rattus Rattus norvegicus Reactive Oxygen Species Recording of previous events Reporting Reproductive Biology Reproductive system Research Research Infrastructure Research Personnel Science Scientist Serum Signal Pathway Signal Transduction Source Staging Steroid biosynthesis Stress Supervision Techniques Telomerase Telomere Shortening Testing Testis Testosterone Time Tissues Training Travel Treatment Protocols United States United States National Institutes of Health Universities Work age related base biological adaptation to stress cell age day density enzyme activity improved indexing leydig interstitial cell male mutant next generation oral communication posters programs receptor expression reproductive reproductive function restraint stress steroid hormone stressor telomere young adult

项目摘要

DESCRIPTION (provided by applicant): Stress is a widespread condition, and is characterized by an over abundance of glucocorticoid activity. Damaging effects of glucocoroticoid overload are evident in many organs including the reproductive system. In the brain, stress-levels of glucocorticoid accelerate hippocampal aging process. One sign of this acceleration is neurodegeneration. This finding has led to the more general proposal that stress accelerates the aging process in other tissues and organs of the body, including the male reproductive system. Stress and aging appear to have inhibitory effects on Leydig cells, which are the primary source of the steroid hormone testosterone. Stress-mediated increases in glucocorticoid levels inhibit steroidogenic enzyme expression resulting in decreased rates of testosterone secretion, following a pattern that is similar to the normal process of Leydig cell aging. We hypothesize that old Leydig, cells are more susceptible to the inhibitory effects of glucocorticoid due to declines in glucocorticoid metabolism by the 11 P -hydroxysteroid dehydrogenase enzyme (11 P -HSD), and chronic stress-mediated increases in glucocorticoid levels may accelerate Leydig cell aging. The lengths of the telomeres of chromosomes shorten as all cells age. Chronic stress has been shown to increase the generation of reactive oxygen species (ROS) in tissues, resulting in a lower telomerase activity, and shorter telomeres. In the present application, the following three Specific Aims will be investigated. 1) We will define age-related changes in glucocorticoid activity and their consequences for testis function. We will test the hypothesis that levels of glucocorticoid activity in the male reproductive system increase during aging by evaluation of the levels of serum glucocorticoid, Leydig cell 110 -HSD enzyme activity and glucocorticoid receptor (GR) numbers. 2) We will test the hypothesis that chronic stress accelerates the degenerative changes associated with Leydig cell aging. This will be approached by observation of Leydig cell aging after a regimen of one-hour of stress over the course of twenty days. 3) Finally, we will measure ROS levels and telomerase activity in Leydig cells after stress and ask whether telomeres are shortened as a result of chronic stress. Based on results shown in other tissues, we expect that stressed-induced declines in Leydig cell telomere length will become established as an underlying event of male reproductive aging.

描述（由申请人提供）：压力是一种普遍的条件，其特征是糖皮质激素活性过高。在包括生殖系统在内的许多器官中，葡萄糖核苷过载的破坏性影响很明显。在大脑中，糖皮质激素的应力水平加速了海马衰老过程。这种加速度的一个迹象是神经变性。这一发现导致了更一般的建议，即压力加速了人体其他组织和器官（包括男性生殖系统）的衰老过程。压力和衰老似乎对leydig细胞具有抑制作用，这是类固醇激素睾丸激素的主要来源。应激介导的糖皮质激素水平的增加抑制类固醇生成酶的表达，导致睾丸激素分泌率降低，遵循与leydig细胞衰老的正常过程相似的模式。 We hypothesize that old Leydig, cells are more susceptible to the inhibitory effects of glucocorticoid due to declines in glucocorticoid metabolism by the 11 P -hydroxysteroid dehydrogenase enzyme (11 P -HSD), and chronic stress-mediated increases in glucocorticoid levels may accelerate Leydig cell aging.随着所有细胞的年龄，染色体的端粒的长度缩短。已显示慢性应激会增加组织中活性氧（ROS）的产生，从而导致端粒酶活性较低，端粒较短。在本应用中，将研究以下三个特定目标。 1）我们将定义与年龄相关的糖皮质激素活性的变化及其对睾丸功能的后果。我们将通过评估血清糖皮质激素水平，Leydig细胞110 -HSD酶活性和糖皮质激素受体（GR）数量来测试假设男性生殖系统中糖皮质激素活性的水平。 2）我们将检验以下假设，即慢性应激加速了与Leydig细胞衰老相关的退化性变化。在二十天的一小时压力方案后，将通过观察Leydig细胞衰老的观察来接近这一点。 3）最后，我们将在压力后测量Leydig细胞中的ROS水平和端粒酶活性，并询问由于慢性应激是否缩短了端粒。基于其他组织中显示的结果，我们预计leydig细胞端粒长度的压力诱导的下降将成为男性生殖衰老的潜在事件。