Rhesus-Human Adrenal Comparisons During Aging

衰老过程中恒河猴与人类肾上腺的比较

基本信息

批准号：
6439122
负责人：
Charles RICHARD PARKER
金额：
$ 7.24万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-06-01 至 2004-05-31
项目状态：
已结题

项目摘要

The factors that regulate the production of adrenal androgens in the human during health and disease are ill defined. Much of the problem in this regard results from a lack of correspondence in the profile of androgens that the human secretes from its adrenal cortex among the commonly utilized experimental animal models. Consequently, the causes for the dramatic deficiency that develops during aging in adrenal secretion of DHEA and DHEA sulfate, the principal secretory products of the human adrenal along with cortisol, remains an unexplained problem in human physiology. It seems quite likely that this deficiency, which in some individuals is equivalent to a 90% reduction in DHEA/DHEA sulfate production compared to that seen in the average young adult, has serious health consequences. In view of the fact that several aspects of the development of the adrenal in the human and other primates are similar, and that adrenal androgen production during fetal development and in adulthood of human and rhesus macaque appear to be quite similar, we propose to investigate the possibility that this animal might be a useful model for study of the regulation of adrenal androgen production in the human and particularly, that the rhesus might be utilized for meaningful studies on the mechanisms of adrenal androgen deficit that occurs during aging as well as providing a model system for evaluation of methods to ameliorate or reverse such changes. DHEA and DHEA sulfate likely arise from the zona reticularis of both the human and rhesus, providing a common focus for hypothesis development and testing. The studies that we propose will involve morphological comparisons of the adrenocortical zones of the young adult rhesus and human, quantitative and qualitative evaluations of the distribution in young adults of both species of key enzymes and co-factors that play important roles in androgen synthesis or that might shunt steroid substrate into alternative biosynthetic pathways, and finally quantitative and qualitative comparisons of aging effects on the morphology and biochemical phenotype of adrenocortical zones of the rhesus compared to that of the human. We hypothesize that there will be found to be sufficient similarities in the rhesus and human to justify the proposal of in-depth studies in the future to address important issues about the mechanisms of adrenal androgen regulation during aging.

在健康和疾病期间调节人类肾上腺雄激素产生的因素尚不明确。这方面的大部分问题是由于常用的实验动物模型中人类从肾上腺皮质分泌的雄激素的分布缺乏对应性所致。因此，衰老过程中肾上腺分泌的 DHEA 和 DHEA 硫酸盐（人类肾上腺与皮质醇的主要分泌产物）严重缺乏的原因仍然是人类生理学中无法解释的问题。这种缺乏似乎很可能会产生严重的健康后果，在某些个体中，这种缺乏相当于 DHEA/DHEA 硫酸盐的产量比普通年轻人减少 90%。鉴于人类和其他灵长类动物的肾上腺发育的几个方面是相似的，并且人类和恒河猴在胎儿发育和成年期间肾上腺雄激素的产生似乎非常相似，我们建议研究这种动物可能是研究人类肾上腺雄激素产生调节的有用模型，特别是恒河猴可能可用于对衰老过程中发生的肾上腺雄激素缺乏机制进行有意义的研究以及提供一个模型系统来评估改善或扭转这种变化的方法。 DHEA 和 DHEA 硫酸盐可能来自人类和恒河猴的网状带，为假设的发展和测试提供了共同的焦点。我们提出的研究将涉及年轻成年恒河猴和人类肾上腺皮质区的形态学比较，定量和定性评估在雄激素合成或雄激素合成中发挥重要作用的关键酶和辅助因子在年轻成年猴中的分布。可能将类固醇底物分流到替代的生物合成途径，最后与恒河猴相比，对衰老对恒河猴肾上腺皮质区的形态和生化表型的影响进行定量和定性比较人类。我们假设，恒河猴和人类之间将会发现足够的相似性，以证明未来进行深入研究的建议是合理的，以解决衰老过程中肾上腺雄激素调节机制的重要问题。