Glutathione deficiency & immune dysfunction during aging

谷胱甘肽缺乏症

• 批准号: 6830308
• 负责人: RUI-MING LIU
• 金额: $ 21.53万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-08 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6830308
• 关键词: age difference; aging; alveolar macrophages; biological models; cysteine; disease /disorder proneness /risk; environmental contamination; gene expression; genetically modified animals; glutamates; glutathione; immunity; immunopathology; laboratory mouse; nitrogen oxides; northern blottings; ozone; respiratory hypersensitivity; respiratory infections; superoxides; western blottings

DESCRIPTION: (provided by applicant) The function of alveolar macrophages (AM), a very important component of lung antibacterial and antiviral defense, decreases with age. Concomitantly, the incidence and the severity of infectious lung diseases increase with age and so does the sensitivity to the acute toxicity of 03 and NO2, two important environmental pollutants, which suppress AM function. The mechanisms underlying such age-associated decline in the immune function of AM and increase in sensitivity to 03 and NO2 toxicity, however, are not clear. Glutathione (GSH), an important antioxidant, plays a critical role in maintaining the optimal function of the immune system. GSH concentration decreases with age while GSH supplementation restores or improves the immune function, especially in the elderly, suggesting a potential involvement of GSH deficiency in age-associated dysfunction of the immune system. Our previous studies further suggest that decreased expression of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in de novo GSH synthesis, is at least partially responsible for age-associated decline in GSH content in rat tissues. However, does GSH content decrease with age in AM? If it does, what is the underlying mechanism? Most importantly, is decreased GSH content responsible for age-associated dysfunction of AM and increased susceptibility of the elderly to infectious lung diseases as well as 03 and NO2 toxicity? All these questions remain to be answered. The specific aims of this project are 1) To determine whether the GSH content in murine AM decreases with age and the potential underlying mechanism. 2) To test the hypothesis that decreased GCS gene expression is responsible for the age-associated decline in GSH content and dysfunction of AM as well as increased sensitivity of the elderly to infectious lung diseases. Tetracycline inducible, macrophage specific GCS sense and antisense gene transgenic mouse models will be used to test this hypothesis. AM function as well as resistance of mice to pneumococci infection will be determined to see whether increasing GCS gene expression and GSH content will restore the function of AM from old mice as well as reduce their lung infection. 3) To determine whether increased sensitivity of the elderly to the acute toxicity caused by 03 or NO2 is due to a decreased GSH content and dysfunction of AM. The long-term objective of this project is to uncover the mechanism underlying dysfunction of AM and increased susceptibility to infectious lung diseases and O3/NO2 toxicity observed in the elderly and to provide therapeutic strategies for treatment of these diseases.

描述：（由申请人提供）肺泡巨噬细胞（AM）的功能， 肺部抗菌和抗病毒防御的一个非常重要的组成部分， 随着年龄的增长而减少。与此同时，传染病的发生率和严重程度 肺部疾病随着年龄的增长而增加，对急性疾病的敏感性也随之增加 03 和 NO2 这两种重要的环境污染物的毒性，抑制 调幅功能。这种与年龄相关的衰退的机制 AM 的免疫功能以及对 03 和 NO2 毒性的敏感性增加， 然而，尚不清楚。谷胱甘肽 (GSH) 是一种重要的抗氧化剂，在 在维持免疫系统最佳功能方面发挥着关键作用。还原型谷胱甘肽 浓度随着年龄的增长而降低，而补充 GSH 可以恢复或改善 免疫功能，尤其是老年人，表明潜在的 GSH 缺乏与年龄相关的免疫功能障碍有关 系统。我们之前的研究进一步表明， γ-谷氨酰半胱氨酸合成酶 (GCS)，从头合成的限速酶 GSH 合成至少部分原因是与年龄相关的 大鼠组织中 GSH 含量。然而，AM 中 GSH 含量是否会随着年龄的增长而减少？ 如果确实如此，其根本机制是什么？最重要的是减少了 GSH 含量与年龄相关的 AM 功能障碍有关，并增加 老年人对传染性肺部疾病以及03和NO2的易感性 毒性？所有这些问题都有待回答。本次活动的具体目标 项目是 1) 确定小鼠 AM 中的 GSH 含量是否随 年龄和潜在的潜在机制。 2）检验假设 GCS 基因表达下降是与年龄相关的功能下降的原因 GSH 含量和 AM 功能障碍以及敏感性增加 老年人易患传染性肺部疾病。四环素诱导型巨噬细胞 特定的 GCS 有义和反义基因转基因小鼠模型将用于 检验这个假设。 AM功能及小鼠对肺炎球菌的抵抗力 将确定感染是否增加GCS基因表达和 GSH含量将恢复老年小鼠的AM功能并减少 他们的肺部感染。 3) 确定是否增加了灵敏度 老年人对03或NO2引起的急性毒性是由于GSH减少所致 AM 的含量和功能障碍。该项目的长期目标是 揭示 AM 功能障碍和易感性增加的潜在机制 老年人中观察到的传染性肺部疾病和 O3/NO2 毒性 为治疗这些疾病提供治疗策略。