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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

ATM Signaling Pathway Acceleration Address Affect Age Aging Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

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项目摘要

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.

项目摘要/摘要阿尔茨海默氏病（AD）是痴呆症的最常见原因，也是与年龄有关的神经系统紊乱。广告不仅会给患者和看护人带来严重的困扰，而且也成为主要的公众健康预测。但是，导致AD发病机理的机制仍不清楚，这是是预防和治疗的主要挑战。越来越多的证据表明功能失调和衰老免疫系统可能是开发AD的主要因素/诱导剂。累积的感觉T细胞在AD患者和老年AD发作小鼠中都已经鉴定出来，但是感觉T细胞增加以及AD发育和进展尚不清楚。我们最近发现了一个人treg细胞可以诱导呼吸器幼稚和效应T细胞的新型抑制作用机制衰老。衰老的T细胞暴露了活性脂质代谢，并具有独特的衰老相关秘书表型（SASP），产生大量的脂质和代谢产物。重要的是，我们最近的研究表明，感觉T细胞可以促进淀粉样蛋白前体蛋白（APP）的聚集，人神经元细胞中的淀粉样蛋白β（Aβ）和tau蛋白。因此，对迫切需要在AD发病机理中的Senscent T细胞的分子和细胞过程，这迫切需要可能导致新颖有效的治疗策略的发展。中心假设提案是：1）脂质代谢过多的积累的感觉T细胞促进了发展和 AD的发病机理； 2）通过脂质重编程在T细胞中的感应阻塞是关键检查点控制AD病理过程和进展，这将为AD预防和免疫疗法。特定目标1试图确定是否具有脂质代谢的感觉T细胞是否是AD发病机理的关键驱动力。我们将剖析秘书脂质的因果关系在神经元细胞的重编程功能中，感觉T细胞的代谢产物。我们还将确定分子和代谢信号传导负责Senscent T诱导的神经元功能变化细胞，导致神经变性和AD发育。特定的目标2将提出完整的体内研究以确定累积的感觉T细胞与AD发育之间的因果关系以及赞助感应加速的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的概念，即T细胞脂质代谢重新编程以逆转T细胞衰老是预防AD免疫疗法的AD开发和增强效率的新型策略。一个这些研究的积极结果应导致对T细胞命运的代谢控制和预防AD和免疫疗法的功能。