Calpain cleavage of α-synuclein and T-cell reactivity in Parkinson’s disease

帕金森病中α-突触核蛋白的钙蛋白酶裂解和 T 细胞反应性

基本信息

  • 批准号:
    10042307
  • 负责人:
  • 金额:
    $ 41.11万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-05-15 至 2024-04-30
  • 项目状态:
    已结题

项目摘要

Summary Parkinson's disease (PD) is a debilitating progressive degenerative movement disorder associated with loss of dopaminergic (DA) neurons in the substantia nigra (SN) along with the accumulation of α-synuclein (α-syn) in the brain, activation of microglia, production of inflammatory cytokines/chemokines, infiltration of CD4+ T-cells, and neurodegeneration. The most potent therapy, L-dopa, does not block disease progression, and the mechanism of the progressive nature is unclear. Calpain, a cysteine protease regulated by calcium, plays a pivotal role in SN and SC (spinal cord) degeneration in PD, and its role in α-syn aggregation, activation of microglia, T cells and their migration indicate calpain to be crucial in promoting the inflammatory process and disease progression. While calpain-1 cleavage of α-syn promotes synuclein aggregation in PD-like diseases, the precise involvement of the two major calpain isoforms, calpain-1 and calpain-2, in α-syn presentation to CD4+ T-cells remains unknown. Preliminary studies here identified a subtype of CD4+ T cells in MPTP mice, which was abolished by calpain inhibitor, suggesting that activation of calpain and CD4+ T cells may play critical roles in the inflammatory process and disease progression in PD. Preliminary data also suggest that siRNA-mediated knockdown of calpain-2 diminishes antigen presentation by human B-cells and inhibits activation of CD4+ T cells. Thus, we hypothesize that activation of distinct calpain isoforms may favor expansion of a subtype of α-syn-reactive CD4+ T cells in PD-like disease. We also hypothesize that calpain inhibition may attenuate α-syn aggregation and expansion of inflammatory T cells, reduce inflammation and support neuronal survival and improved outcome in PD patients. Two specific aims are proposed to test the hypothesis: (Aim 1) To investigate whether activation of calpain-1 or calpain-2 is linked with microglial presentation of α-syn to CD4+ T cells resulting in disease progression and neurodegeneration in PD-like disease in mice. (Aim 2) To determine whether inhibition of calpain-2 reduces microglial presentation of α-syn and generation of pathogenic CD4+ T cells, attenuating disease progression in mouse models of PD. The goal of this study is to investigate the role of calpain-1 and calpain-2 in generating α-syn-reactive pathogenic CD4+ T cells, and whether a subpopulation of CD4+ T cells from MPTP mice can induce PD-like disease in immunodeficient mice. Studies are planned to determine whether deletion of calpain-1 attenuates α-syn aggregation and expansion of CD4+ T cells using calpain-1 knockout (KO) mice. In addition, the role of calpain-2 inhibitor will be assessed in the study of alteration of inflammatory CD4+ T cell response and production of cytokines/chemokines in calpain-1 KO mice. Testing the effects of distinct calpain isoforms in the generation of α-syn-reactive pathogenic T cells and induction neuronal death and degeneration may lead to development of a novel approach for treating PD as well as other neurodegenerative disorders.
总结 帕金森氏病(PD)是一种使人衰弱的进行性退行性运动障碍, 黑质(SN)多巴胺(DA)能神经元沿着α-突触核蛋白(α-syn)的蓄积, 脑,小胶质细胞的活化,炎性细胞因子/趋化因子的产生,CD 4 + T细胞的浸润, 和神经退化最有效的治疗,左旋多巴,不能阻止疾病的进展, 渐进性的机制尚不清楚。钙蛋白酶是一种受钙调节的半胱氨酸蛋白酶, 在PD的SN和SC(脊髓)变性中的关键作用,以及其在α-syn聚集、 小胶质细胞、T细胞及其迁移表明钙蛋白酶在促进炎症过程中至关重要, 疾病进展。虽然钙蛋白酶-1切割α-syn促进PD样疾病中的突触核蛋白聚集, 两种主要的钙蛋白酶亚型,钙蛋白酶-1和钙蛋白酶-2,在α-syn呈递中的精确参与, CD 4 + T细胞仍然未知。初步研究在MPTP小鼠中鉴定了一种CD 4 + T细胞亚型, 钙蛋白酶抑制剂可消除这种抑制作用,这表明钙蛋白酶和CD 4 + T细胞的激活可能起作用。 在PD的炎症过程和疾病进展中起关键作用。初步数据还表明, siRNA介导的钙蛋白酶-2敲低减少人B细胞的抗原呈递并抑制 活化CD 4 + T细胞。因此,我们假设不同的钙蛋白酶亚型的激活可能有利于 PD样疾病中α-syn-reactive CD 4 + T细胞亚型的扩增我们还假设钙蛋白酶 抑制可以减弱α-syn聚集和炎性T细胞的扩增,减少炎症, 支持PD患者的神经元存活和改善的结果。提出了两个具体目标,以测试 假设:(目的1)研究calpain-1或calpain-2的激活是否与小胶质细胞 α-syn向CD 4 + T细胞递呈,导致PD样患者疾病进展和神经退行性变 老鼠的疾病(Aim 2)确定抑制钙蛋白酶-2是否减少α-syn的小胶质细胞呈递 和致病性CD 4 + T细胞的产生,减弱PD小鼠模型中的疾病进展。目标 本研究的目的是探讨钙蛋白酶-1和钙蛋白酶-2在产生α-syn-reactive致病性CD 4+中的作用。 T细胞,以及来自MPTP小鼠的CD 4 + T细胞亚群是否可以诱导PD样疾病。 免疫缺陷小鼠研究计划确定是否删除钙蛋白酶-1减弱α-syn 使用钙蛋白酶-1敲除(KO)小鼠的CD 4 + T细胞的聚集和扩增。此外, 钙蛋白酶-2抑制剂将在炎性CD 4 + T细胞应答改变的研究中进行评估, 在钙蛋白酶-1 KO小鼠中细胞因子/趋化因子的产生。测试不同的钙蛋白酶同种型在细胞中的作用, α-syn-reactive致病性T细胞的产生和诱导神经元死亡和变性可能导致 开发用于治疗PD以及其他神经退行性疾病的新方法。

项目成果

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NAREN L BANIK其他文献

NAREN L BANIK的其他文献

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{{ truncateString('NAREN L BANIK', 18)}}的其他基金

Research Career Scientist for Naren Banik, PhD
Naren Banik 博士的研究职业科学家
  • 批准号:
    10593090
  • 财政年份:
    2022
  • 资助金额:
    $ 41.11万
  • 项目类别:
Research Career Scientist for Naren Banik, PhD
Naren Banik 博士的研究职业科学家
  • 批准号:
    10476736
  • 财政年份:
    2022
  • 资助金额:
    $ 41.11万
  • 项目类别:
Attenuation of Inflammatory Response in Progressive Neurodegeneration in Parkinson's Disease
帕金森病进行性神经变性中炎症反应的减弱
  • 批准号:
    10158428
  • 财政年份:
    2019
  • 资助金额:
    $ 41.11万
  • 项目类别:
Attenuation of Inflammatory Response in Progressive Neurodegeneration in Parkinson's Disease
帕金森病进行性神经变性中炎症反应的减弱
  • 批准号:
    10731055
  • 财政年份:
    2019
  • 资助金额:
    $ 41.11万
  • 项目类别:
Attenuation of Inflammatory Response in Progressive Neurodegeneration in Parkinson's Disease
帕金森病进行性神经变性中炎症反应的减弱
  • 批准号:
    9918754
  • 财政年份:
    2019
  • 资助金额:
    $ 41.11万
  • 项目类别:
Regulation of inflammatory T Cells and Neuroprotection by Calpain Inhibitor in MS
多发性硬化症中钙蛋白酶抑制剂对炎症 T 细胞的调节和神经保护作用
  • 批准号:
    9339545
  • 财政年份:
    2014
  • 资助金额:
    $ 41.11万
  • 项目类别:
Regulation of inflammatory T Cells and Neuroprotection by Calpain Inhibitor in MS
多发性硬化症中钙蛋白酶抑制剂对炎症 T 细胞的调节和神经保护作用
  • 批准号:
    8842002
  • 财政年份:
    2014
  • 资助金额:
    $ 41.11万
  • 项目类别:
Hormonal Intervention Protects Axon-myelin to Promote Functional Recovery in SCI
激素干预保护轴突髓磷脂,促进 SCI 功能恢复
  • 批准号:
    10700378
  • 财政年份:
    2012
  • 资助金额:
    $ 41.11万
  • 项目类别:
Hormonal Intervention Protects Axon-myelin to Promote Functional Recovery in SCI
激素干预保护轴突髓磷脂,促进 SCI 功能恢复
  • 批准号:
    10291814
  • 财政年份:
    2012
  • 资助金额:
    $ 41.11万
  • 项目类别:
Hormonal Intervention Protects Axon-myelin to Promote Functional Recovery in SCI
激素干预保护轴突髓磷脂,促进 SCI 功能恢复
  • 批准号:
    8597921
  • 财政年份:
    2012
  • 资助金额:
    $ 41.11万
  • 项目类别:

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