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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不明确。这方面的大部分问题是由于在常用的实验动物模型中，人从其肾上腺皮质分泌的雄激素的分布缺乏对应性。因此，在衰老过程中肾上腺分泌DHEA和DHEA硫酸盐（人肾上腺沿着皮质醇的主要分泌产物）显著不足的原因仍然是人类生理学中一个无法解释的问题。这似乎很可能是这种缺陷，这在一些人相当于减少90%的DHEA/DHEA硫酸盐生产相比，看到的平均年轻人，有严重的健康后果。鉴于人类和其他灵长类动物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期间和成年期的肾上腺雄激素产生似乎非常相似，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的可能性，特别是，恒河猴可用于对衰老过程中发生的肾上腺雄激素缺乏的机制进行有意义的研究，并为评估改善或逆转此类变化的方法提供模型系统。 DHEA和DHEA硫酸盐可能来自人类和恒河猴的网状内皮细胞，为假设开发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，对两种关键酶和辅因子在年轻成年人中的分布进行定量和定性评价，这些酶和辅因子在雄激素合成中起重要作用，或者可能将类固醇底物分流到替代生物合成途径中，最后，定量和定性比较衰老对恒河猴和人类肾上腺皮质区形态和生化表型的影响。我们假设，将发现在恒河猴和人类有足够的相似性，以证明在未来的深入研究的建议，以解决在衰老过程中肾上腺雄激素调节机制的重要问题。