Metabolic Control of T Cell Senescence in Pathogenesis and Immunotherapy of Alzheimer's Disease

阿尔茨海默病发病机制和免疫治疗中 T 细胞衰老的代谢控制

• 批准号: 10830669
• 负责人: Guangyong Peng
• 金额: $ 38.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10830669
• 关键词: ATM Signaling Pathway; Acceleration; Address; Affect; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Area; Binding; CD8-Positive T-Lymphocytes; Caregivers; Cell Aging; Cell physiology; Cells; Cellular Structures; DNA Damage; Dementia; Development; Diagnostic; Disease Progression; Distress; Enzymes; Etiology; Exhibits; Functional disorder; Goals; Human; Immune; Immune system; Immunotherapy; Knowledge; Lipids; MAP Kinase Gene; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Onset of illness; Outcome Study; Pathogenesis; Pathologic Processes; Patients; Phenotype; Population; Process; Public Health; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Up-Regulation; Writing; adaptive immunity; age related; aged; disorder control; effector T cell; improved; in vivo; lipid metabolism; mouse model; nervous system disorder; novel; novel strategies; p38 Mitogen Activated Protein Kinase; peripheral blood; prevent; programs; response; senescence; tau Proteins; therapeutically effective

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the most common cause of dementia, and also an age-related neurological disorder. AD not only causes severe distress for patients and caregivers, but it also becomes a major public health predicament. However, the mechanisms responsible for the pathogenesis of AD are still unclear, which is a major challenge for AD prevention and therapy. Increasing evidence suggests that dysfunctional and aging immune system may be a primary factor/inducer for the development of AD. Accumulated senescent T cells have been identified in both AD patients and in aged AD onset mice, but the causative relationship between the increased senescent T cells and AD development and progression is unknown. We recently discovered a novel suppressive mechanism that human Treg cells can induce responder naïve and effector T cell senescence. Senescent T cells exhibit active lipid metabolism and possess a unique senescence-associated secretory phenotype (SASP), producing high amounts of lipids and metabolites. Importantly, our more recent studies demonstrated that senescent T cells can promote the aggregation of amyloid precursor protein (APP), amyloid beta (Aβ) and Tau proteins in human neuronal cells. Therefore, an improved understanding of the molecular and cellular processes of senescent T cells in the pathogenesis of AD is urgently needed, which could lead to the development of novel and effective therapeutic strategies. The central hypotheses of this proposal are: 1) accumulated senescent T cells with excessive lipid metabolism promote the development and pathogenesis of AD; and 2) blockage of senescence in T cells via lipid reprogramming is a critical checkpoint to control AD pathologic processes and progression, which will provide a novel strategy for AD prevention and immunotherapy. Specific Aim 1 seeks to determine whether senescent T cells with lipid metabolism disorder are a critical driver for the pathogenesis of AD. We will dissect the causative role of the secretory lipid metabolites of senescent T cells in reprogramming functions of neuronal cells. We will also identify the molecular and metabolic signaling responsible for the functional changes in neurons induced by senescent T cells, resulting in neurodegeneration and AD development. Specific Aim 2 will propose complementary in vivo studies to identify the causative relationship between the accumulated senescent T cells and AD development and disease progression in a spontaneous senescence accelerated SAMP8 mouse model. We will then test our hypothesis and the novel concept that that reprogramming of T cell lipid metabolism to reverse T cell senescence is a novel strategy to prevent AD development and enhance efficacy for AD immunotherapy. A positive outcome of these studies should lead to novel strategies for metabolic control of T cell fate and function for AD prevention and immunotherapy.

项目概要/摘要 阿尔茨海默病（AD）是痴呆症最常见的原因，也是一种与年龄相关的神经系统疾病 紊乱。 AD 不仅给患者和护理人员带来严重的痛苦，而且还成为一个主要的公众 健康困境。然而，AD的发病机制仍不清楚，其中 是AD预防和治疗的重大挑战。越来越多的证据表明功能失调和衰老 免疫系统可能是 AD 发生的主要因素/诱导因素。累积的衰老T细胞 已在 AD 患者和老年 AD 发病小鼠中发现，但两者之间的因果关系 衰老T细胞的增加与AD的发生和进展之间的关系尚不清楚。我们最近发现了一个 人类 Treg 细胞可诱导反应幼稚 T 细胞和效应 T 细胞的新抑制机制 衰老。衰老T细胞表现出活跃的脂质代谢并具有独特的衰老相关性 分泌表型（SASP），产生大量脂质和代谢物。重要的是，我们最近 研究表明，衰老的T细胞可以促进淀粉样前体蛋白（APP）的聚集， 人类神经元细胞中的淀粉样蛋白 (Aβ) 和 Tau 蛋白。因此，加深了对 迫切需要研究衰老 T 细胞在 AD 发病机制中的分子和细胞过程， 可能会导致新颖且有效的治疗策略的发展。本研究的中心假设 建议是：1）积累的衰老T细胞与过度的脂质代谢促进发育和 AD 的发病机制； 2) 通过脂质重编程阻断 T 细胞衰老是一个关键检查点 控制AD病理过程和进展，为AD预防和治疗提供新策略 免疫疗法。具体目标1旨在确定衰老T细胞是否患有脂质代谢紊乱 是 AD 发病机制的关键驱动因素。我们将剖析分泌脂质的致病作用 衰老 T 细胞的代谢物在神经元细胞重编程功能中的作用。我们还将确定 分子和代谢信号传导导致衰老 T 诱导的神经元功能变化 细胞，导致神经变性和 AD 发展。具体目标2将提出体内补充 研究确定累积的衰老 T 细胞与 AD 发展之间的因果关系 自发衰老加速 SAMP8 小鼠模型中的疾病进展。然后我们将测试 我们的假设和新概念是，T 细胞脂质代谢重编程可逆转 T 细胞 衰老是预防 AD 发展和增强 AD 免疫治疗疗效的新策略。一个 这些研究的积极成果应该会带来 T 细胞命运代谢控制的新策略， AD预防和免疫治疗的功能。