Determining the mechanism of alpha-synuclein dependent innate immune responses in the brain

确定大脑中α-突触核蛋白依赖性先天免疫反应的机制

基本信息

  • 批准号:
    10461531
  • 负责人:
  • 金额:
    $ 39.7万
  • 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:
    2022-04-01 至 2027-03-31
  • 项目状态:
    未结题

项目摘要

Project Summary The nervous system was traditionally thought to act independently of an organism’s immune response and be an “immune privileged site”. Increasing scientific evidence has shown that the nervous system is not immune privileged but instead has a unique immune response that is critical for maintaining homeostasis and critical for central nervous system (CNS) function. Much of the work in the field of neuroinflammation has focused on the function of microglia, but little is known about the role of neurons in modulating neuroinflammatory responses in the CNS. Five years ago, we discovered that the neuronal protein, alpha-synuclein(asyn), was critical in protecting neurons from viral infection. We have extended these data to show that ayn modulates type 1 interferon (T1IFN) signaling. Asyn is known as a cause of Parkinson’s disease (PD) and is known to be dysregulated in neurodegenerative diseases, traumatic brain injury, and other diverse CNS diseases. Despite the importance of asyn in CNS disease states, the functional role of asyn expression is not well understood. We have discovered that asyn expression is necessary to support expression of specific interferon stimulated genes (ISGs) in the brain during T1IFN signaling, independent of microglia activation. Using induced pluripotent stem cells (iPSC) and CRISPR-mediated SNCA deletion to create asyn KO human dopaminergic neurons, we found that viral growth in neurons is inhibited in the presence of asyn expression and that viral- induced ISGs such as IFIT1, OAS1, and TRIM25 exbibit decreased expression in asyn KO neurons. We next found that asyn KO neurons exhibit a broad loss of ISG expression following treatment with poly I:C or type 1 interferon (2) treatment due to loss of asyn-dependent STAT2 activation and asyn nuclear localization. Taken together, our data show for the first time that asyn functions to support interferon responses in neurons. The goal of this proposal is to determine the specific mechanism of asyn-dependent innate immune responses in neurons. We hypothesize that asyn is a novel neuron-intrinsic regulator of the CNS innate immune response. We will test our hypothesis in three aims. Aim 1 will use asyn KO and WT human neurons to define the specific interactions between asyn, interferon signaling, and vesicle transport in neurons. Aim 2 will define the role of neuron-intrinsic asyn production on the innate T-cell response in the brain using an inducible, nestin-Cre-lox knockout of the asyn gene (Snca) in mice. Aim 3 will evaluate PD-specific and species specific changes in asyn that may influence its native function in neurons. Taken together, the proposed studies will significantly advance our understanding of neuron-intrinsic control of the innate immune response in the CNS and provide novel insight into the underlying immunopathogenesis that contributes to diverse human diseases of the CNS.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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John David Beckham其他文献

John David Beckham的其他文献

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{{ truncateString('John David Beckham', 18)}}的其他基金

Determining the mechanism of alpha-synuclein dependent innate immune responses in the brain
确定大脑中α-突触核蛋白依赖性先天免疫反应的机制
  • 批准号:
    10590623
  • 财政年份:
    2022
  • 资助金额:
    $ 39.7万
  • 项目类别:
Development of a vaccination platform for emerging flavivirus infections
开发新发黄病毒感染疫苗接种平台
  • 批准号:
    10380498
  • 财政年份:
    2021
  • 资助金额:
    $ 39.7万
  • 项目类别:
Development of a vaccination platform for emerging flavivirus infections
开发新发黄病毒感染疫苗接种平台
  • 批准号:
    10520064
  • 财政年份:
    2021
  • 资助金额:
    $ 39.7万
  • 项目类别:
Defining the Mechanism of Alpha-synuclein Dependent Restriction of Viral Neuroinvasion
定义α-突触核蛋白依赖性限制病毒神经侵袭的机制
  • 批准号:
    9349196
  • 财政年份:
    2017
  • 资助金额:
    $ 39.7万
  • 项目类别:
Targeting Innate Immunity as A Therapeutic Intervention for Parkinsons Disease
针对先天免疫作为帕金森病的治疗干预措施
  • 批准号:
    10356058
  • 财政年份:
    2017
  • 资助金额:
    $ 39.7万
  • 项目类别:
Mechanisms of Apoptosis in Virus-Infected Neurons
病毒感染神经元的凋亡机制
  • 批准号:
    8113650
  • 财政年份:
    2010
  • 资助金额:
    $ 39.7万
  • 项目类别:
Mechanisms of Apoptosis in Virus-Infected Neurons
病毒感染神经元的凋亡机制
  • 批准号:
    7919751
  • 财政年份:
    2009
  • 资助金额:
    $ 39.7万
  • 项目类别:
Mechanisms of Apoptosis in Virus-Infected Neurons
病毒感染神经元的凋亡机制
  • 批准号:
    8065347
  • 财政年份:
    2008
  • 资助金额:
    $ 39.7万
  • 项目类别:
Mechanisms of Apoptosis in Virus-Infected Neurons
病毒感染神经元的凋亡机制
  • 批准号:
    7807965
  • 财政年份:
    2008
  • 资助金额:
    $ 39.7万
  • 项目类别:
Mechanisms of Apoptosis in Virus-Infected Neurons
病毒感染神经元的凋亡机制
  • 批准号:
    8260229
  • 财政年份:
    2008
  • 资助金额:
    $ 39.7万
  • 项目类别:

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