MITOCHONDRIAL DYSFUNCTION IN IMMUNOSENESCENCE

免疫衰老中的线粒体功能障碍

• 批准号: 2055760
• 负责人: HAGAI ROTTENBERG
• 金额: $ 18.49万
• 依托单位: ALLEGHENY UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-15 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2055760
• 关键词: B lymphocyte; T lymphocyte; acidity /alkalinity; aging; bioenergetics; biological signal transduction; calcium; cellular respiration; divalent cations; flow cytometry; hydrogen transporting ATP synthase; ion transport; laboratory mouse; lymphocyte proliferation; macrophage; membrane channels; membrane potentials; mitochondria; mitochondrial membrane; mitogens; natural killer cells; oxidative phosphorylation; phosphorylation; respiratory enzyme; tissue /cell preparation

Age-dependent immune dysfunction, immunosenescence, may contribute to the increased incidence of cancer and other age-related diseases in old people. It is believed that many age-related diseases are caused by accumulation of oxidative damage from oxygen free radicals. In particular, the mitochondrion, the major site of free radical generation in the cell, is susceptible to oxidative damage to its' DNA as well as proteins and lipids, and mitochondrial dysfunction is thus believed to play a major role in aging, and-age-related diseases. Immunosenescence have been studied extensively in splenic T cells from old mice, in which, the response to stimuli is greatly attenuated. This is, partially, the result of inhibition early signaling events (e.g the rise in cytoplasmic free Ca2+, protein phosphorylation) but also several additional defects. We suggest that some of these defects are the result of mitochondrial dysfunction. Thus, the inhibition of Ca2+ signaling may be due to modulation of mitochondrial calcium metabolism while the inhibition of protein phosphorylation may result from inhibition of ATP synthesis. The age-dependent alterations in lymphocytes subsets may also result from mitochondrial-dependent aberrations of programmed cell death. To test the hypothesis we shall study splenic lymphocytes from young and old mice and characterize the activities of the systems of oxidative phosphorylation (e.g. respiratory complexes, ATP synthase), the phosphate potential, pH1, mitochondrial membrane potential and mitochondrial calcium metabolism uptake and efflux systems, the megachannel). These studies will progress from whole cells to saponinpermeabilized cells and isolated mitochondria. Initially these experiments will be carried-out with unfractionated lymphocyte populations and later selective experiments will be carried-out with lymphocyte subsets (e.g. B and T cells, naive and memory T cells, cytotoxic T cells) and also with other cells of the immune system (e.g. macrophages and NK cells). These experiments should elucidate the role of mitochondrial dysfunction in immunosenescence and may lead to new strategies in prevention of cancer and other age-related diseases.

年龄依赖性免疫功能障碍，免疫衰老，可能有助于 老年人的癌症发生率和其他与年龄有关的疾病的发病率增加。 据信，许多与年龄有关的疾病是由积累引起的 氧化自由基的氧化损伤。特别是 线粒体是细胞中自由基的主要部位，是 容易受到其'DNA以及蛋白质和脂质的氧化损害， 因此，线粒体功能障碍被认为在 衰老和与年龄有关的疾病。 免疫已在旧的脾T细胞中进行了广泛研究 小鼠对刺激的反应大大减弱。这是， 部分地，抑制早期信号事件的结果（例如上升 在细胞质游离Ca2+中，蛋白质磷酸化），但也有几个 其他缺陷。我们建议其中一些缺陷是结果 线粒体功能障碍。因此，CA2+信号的抑制可能 是由于线粒体钙代谢的调节而引起的 抑制蛋白质磷酸化可能是由于抑制ATP而引起的 合成。淋巴细胞子集的年龄依赖性改变也可能 线粒体依赖性细胞死亡的畸变引起的。 为了检验假设，我们将研究来自年轻人的脾淋巴细胞 老鼠并表征了氧化系统的活性 磷酸化（例如呼吸络合物，ATP合酶），磷酸盐 电位，PH1，线粒体膜电位和线粒体钙 代谢摄取和外排系统，巨型通道）。这些研究会 从全细胞到皂苷的细胞和分离的细胞发展 线粒体。 最初，这些实验将进行 未分流的淋巴细胞种群和后来的选择性实验将 用淋巴细胞亚群（例如B和T细胞，幼稚和 记忆T细胞，细胞毒性T细胞）以及免疫的其他细胞 系统（例如巨噬细胞和NK细胞）。 这些实验应阐明 线粒体功能障碍在免疫衰老中的作用，可能导致 预防癌症和其他与年龄有关的疾病的新策略。