AGE-RELATED CHANGES IN GLUTATHIONE METABOLISM

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 氧化应激被认为是导致特定疾病的开始或进展以及衰老的一般过程的机制之一。 谷胱甘肽（GSH）是一种在所有哺乳动物细胞中以高浓度存在的三肽，是人体主要的内源性抗氧化剂，在解毒反应和保护细胞免受氧化剂的毒性作用中起着至关重要的作用。 体内GSH储存的维持是一个复杂的综合现象，人们对可能调节全身和特定组织和细胞中GSH水平的潜在干预措施重新产生了兴趣。 已知与氧化应激增加相关的年龄增长也被报道与心血管疾病、葡萄糖耐量受损和糖尿病相关;后者也被证明伴随着较低的GSH浓度。 可能导致GSH状态受损的机制包括合成减少和/或相对于合成能力的利用增加。 理想情况下，人们希望测量GSH合成和利用的体内速率。 不幸的是，众多的途径消耗GSH，以及组织的变化，使得它不可能有意义的同时测量的利用所有不同的途径在人类。 因此，本提案的重点将放在GSH合成率上。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Oxidative stress is thought to be one of the mechanisms leading to the initiation or progression of specific diseases as well as to the general process of aging. Glutathione (GSH), a tripeptide present in high concentrations in all mammalian cells, is the body's major endogenous antioxidant and plays a vital role in detoxification reactions and in the protection of cells from the toxic effects of oxidants. Maintenance of body GSH stores is a complex, integrated phenomenon, and there has been a resurgence of interest in potential interventions that may modulate GSH levels in the whole body and in specific tissues and cells. Advancing age, known to be associated with increased oxidative stress, is also reported to be associated with cardiovascular disease, impaired glucose tolerance, and diabetes mellitus; the latter has also been shown to be accompanied by lower GSH concentrations. The mechanisms that could be responsible for a compromised GSH status include decreased synthesis and/or increased utilization relative to synthetic capacity. Ideally, one would like to measure in vivo rates of both GSH synthesis and utilization. Unfortunately, the multitude of pathways consuming GSH, as well as tissue variation, makes it impossible to have meaningful simultaneous measurements of utilization by all of the different pathways in the human. Hence, the focus of this proposal will be on GSH synthesis rates.