Role of Autophagy in T Cell Function and Immunosenescence (Project 3)

自噬在 T 细胞功能和免疫衰老中的作用（项目 3）

基本信息

批准号：
9142593
负责人：
Fernando Macian
金额：
$ 22.18万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-15 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9142593
关键词：
Address Affect Age Aging Aging-Related Process Amino Acids Animals Antioxidants Autophagocytosis Bioenergetics Cell Aging Cell physiology Cells Characteristics Chronic Collaborations Data Defect Deterioration Development Elderly Energy-Generating Resources Funding Homeostasis Immune response Immune system Immunity Immunization Infection Interleukin-2 Intervention Lipids Maintenance Malignant Neoplasms Mediating Membrane Metabolism Molecular Molecular Chaperones Morbidity - disease rate Mus Normal Cell Organism Output Oxidative Stress Pathway interactions Play Predisposition Process Production Protein Biosynthesis Proteins Receptor Signaling Recycling Regulation Rodent Role Signal Pathway Signal Transduction Stress Substrate Specificity System T cell response T-Cell Proliferation T-Cell Receptor T-Lymphocyte Transcriptional Regulation Transgenic Organisms Translating Vaccination Work age effect age related aged anti aging cell age cytokine extracellular feeding schedule functional decline immune function immunosenescence improved in vivo mortality mouse model novel therapeutic intervention pathogen programs protein degradation receptor response restoration stressor tumor

项目摘要

Project Summary Immunosenescence defines the changes in the immune system associated with age that are responsible for the age-dependent defects in the ability to respond to pathogens and develop effective responses to vaccination in the elderly. Both the innate and the adaptive immune system show functional defects with age, with T cells' function being specially affected. The molecular mechanisms that are responsible for defective T cell function are however not yet fully understood. Lysosomal degradation of proteins via autophagy has been shown to play a key role in maintaining normal cell homeostasis by reducing the accumulation of damaged proteins. Autophagy also plays an important role in the regulation of cell protein levels in response to extracellular signals, and has been implicated in the control of T cell homeostasis. In collaboration with P1 and P2 in this Program Project (PP), we have shown that macroautophagy and chaperone mediated autophagy are both activated in response to TCR engagement and play key roles in the regulation of the maintenance of the bioenergetics output in activated T cells and in the regulation of signaling cascades downstream of the TCR, respectively. Interestingly the activity of these pathways is reduced in T cells from aged mice and its restoration leads to improve activation-induced responses in aged T cells. Furthermore, working with P4 we have found that the activity of both pathways appears to respond to lipid and oxidative stress, both characteristic of the aging process. In this proposal we intend to elucidate the molecular mechanisms that regulate the different forms of autophagy in T cells and characterize how the age-associated decline in autophagy may determine the development of deficient T cell responses. We will also study how increased chronic pathogen, lipid and oxidative stress in aging may contribute to the decreased activity of macroautophagy and/or chaperone mediated autophagy with age. Finally, using mouse models, we will study the possibility ofrestoring autophagic activity in old rodents to improve T cell-mediated responses in vivo. Relevance: Understanding the molecular mechanism that are responsible for reduced immunity in old organisms should prove valuable in the development of new therapeutic interventions aimed at restoring normal immune function and therefore reduce morbidity and mortality in the elderly. .

项目概要免疫衰老定义了与年龄相关的免疫系统的变化，这些变化负责对病原体作出反应和对疫苗接种产生有效反应的能力的年龄依赖性缺陷在老年人中。随着年龄的增长，先天免疫系统和适应性免疫系统都会出现功能缺陷，其中 T 细胞功能受到特别影响。导致 T 细胞功能缺陷的分子机制但尚未完全了解。溶酶体通过自噬降解蛋白质已被证明发挥作用通过减少受损蛋白质的积累，在维持正常细胞稳态中发挥关键作用。自噬在响应细胞外信号调节细胞蛋白水平方面也发挥着重要作用，并与 T 细胞稳态的控制有关。与本计划中的 P1 和 P2 合作项目（PP），我们已经证明巨自噬和分子伴侣介导的自噬均在对 TCR 参与的反应并在生物能维持的调节中发挥关键作用分别在激活的 T 细胞和 TCR 下游信号级联的调节中产生输出。有趣的是，这些通路的活性在衰老小鼠的 T 细胞中降低，而其恢复则导致改善老化 T 细胞的激活诱导反应。此外，通过与 P4 合作，我们发现这两种途径的活性似乎都对脂质和氧化应激作出反应，这都是衰老的特征过程。在本提案中，我们打算阐明调节不同形式的分子机制 T 细胞中的自噬，并描述与年龄相关的自噬下降如何决定 T 细胞反应的发展有缺陷。我们还将研究慢性病原体、脂质和衰老过程中的氧化应激可能导致巨自噬和/或伴侣蛋白活性降低随着年龄的增长介导自噬。最后，我们将利用小鼠模型，研究恢复自噬的可能性。在老年啮齿动物中的活性可改善体内 T 细胞介导的反应。相关性：了解导致老年人免疫力下降的分子机制生物体应该在开发旨在恢复正常的新治疗干预措施中具有价值免疫功能，从而降低老年人的发病率和死亡率。。