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）肺泡巨噬细胞的功能（AM）， 肺抗菌和抗病毒防御的非常重要的组成部分， 随着年龄的增长而减小。同时，传染性的发病率和严重程度 肺部疾病随着年龄的增长而增加，对急性的敏感性也会增加 03和No2的毒性，两种重要的环境污染物，它们抑制 AM功能。这种与年龄相关下降的机制 AM的免疫功能以及对03和NO2毒性的敏感性的增加， 但是，尚不清楚。谷胱甘肽（GSH）是一种重要的抗氧化剂，可发挥A 在维持免疫系统的最佳功能中的关键作用。 GSH 浓度随着年龄的增长而降低，而GSH补充恢复或改善 免疫功能，尤其是在老年人中，表明潜力 GSH缺乏症参与免疫与年龄相关的功能障碍 系统。我们先前的研究进一步表明， γ-谷氨酰半胱氨酸合成酶（GCS），从头开始的速率限制酶 GSH合成至少部分负责与年龄相关的下降 大鼠组织中的GSH含量。但是，GSH含量会随​​着AM的年龄而降低吗？ 如果是这样，那么基本机制是什么？最重要的是，减少了 GSH含量负责与年龄相关的AM功能障碍并增加 老年人对传染性肺部疾病以及03和NO2的敏感性 毒性？所有这些问题仍有待回答。这个特定的目的 项目是1）确定鼠中的GSH含量是否随着 年龄和潜在的潜在机制。 2）检验以下假设 GCS基因表达降低是导致年龄相关的下降 AM的GSH含量和功能障碍以及提高的灵敏度 老年人到传染性肺部疾病。四环素可诱导，巨噬细胞 特定的GCS感官和反义基因转基因小鼠模型将用于 检验此假设。 AM功能以及小鼠对肺炎球菌的抗性 感染将确定以查看增加GCS基因表达和 GSH含量将恢复旧鼠的AM功能，并减少 他们的肺部感染。 3）确定是否提高了对 老年人对由03或NO2引起的急性毒性是由于GSH降低 AM的内容和功能障碍。该项目的长期目标是 发现AM功能障碍的基础机制和增加的敏感性 感染性肺部疾病和O3/NO2毒性在老年人和 提供治疗这些疾病的治疗策略。