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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

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.

项目总结/文摘