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:
  • 金额:
    $ 38.88万
  • 依托单位:
  • 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

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

项目成果

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Guangyong Peng其他文献

Guangyong Peng的其他文献

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{{ truncateString('Guangyong Peng', 18)}}的其他基金

Excessive lipid metabolism in T cell senescence and immunosuppression
T细胞衰老和免疫抑制中的过度脂质代谢
  • 批准号:
    10735675
  • 财政年份:
    2023
  • 资助金额:
    $ 38.88万
  • 项目类别:
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:
    10516392
  • 财政年份:
    2022
  • 资助金额:
    $ 38.88万
  • 项目类别:
Targeting T Cell Senescence and Dysfunction for Anti-tumor Immunity
针对 T 细胞衰老和功能障碍的抗肿瘤免疫
  • 批准号:
    10557127
  • 财政年份:
    2020
  • 资助金额:
    $ 38.88万
  • 项目类别:
Metabolic Control of Innate and Adaptive Immunity in Breast Cancer
乳腺癌先天性和适应性免疫的代谢控制
  • 批准号:
    9885847
  • 财政年份:
    2020
  • 资助金额:
    $ 38.88万
  • 项目类别:
Targeting T Cell Senescence and Dysfunction for Anti-tumor Immunity
针对 T 细胞衰老和功能障碍的抗肿瘤免疫
  • 批准号:
    10361444
  • 财政年份:
    2020
  • 资助金额:
    $ 38.88万
  • 项目类别:
Role of Senescent T cells in Alzheimer's Disease
衰老 T 细胞在阿尔茨海默病中的作用
  • 批准号:
    9975395
  • 财政年份:
    2020
  • 资助金额:
    $ 38.88万
  • 项目类别:
Metabolic Control of Innate and Adaptive Immunity in Breast Cancer
乳腺癌先天性和适应性免疫的代谢控制
  • 批准号:
    10341107
  • 财政年份:
    2020
  • 资助金额:
    $ 38.88万
  • 项目类别:
Metabolic Control of Innate and Adaptive Immunity in Breast Cancer
乳腺癌先天性和适应性免疫的代谢控制
  • 批准号:
    10547790
  • 财政年份:
    2020
  • 资助金额:
    $ 38.88万
  • 项目类别:
Targeting T Cell Senescence and Dysfunction for Anti-tumor Immunity
针对 T 细胞衰老和功能障碍的抗肿瘤免疫
  • 批准号:
    9981183
  • 财政年份:
    2020
  • 资助金额:
    $ 38.88万
  • 项目类别:
Gamma/Delta Treg Cells and Human Breast Cancer
γ/δ Treg 细胞与人类乳腺癌
  • 批准号:
    9024480
  • 财政年份:
    2015
  • 资助金额:
    $ 38.88万
  • 项目类别:

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