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
- 来源:
- 关键词:Antigen PresentationAssesAttenuatedAutopsyB-LymphocytesBCL2 geneBiological MarkersBone MarrowBrainCD4 Positive T LymphocytesCalciumCalpainCaspaseCell DeathCellsCytoprotectionDataDevelopmentDiseaseDisease ProgressionDopaminergic CellFlow CytometryGenerationsGoalsHumanImmunodeficient MouseImmunohistochemistryIn VitroInfiltrationInflammationInflammatoryKnock-outKnockout MiceLeadLevodopaLinkMediatingMicrogliaMovement DisordersMusNatureNerve DegenerationNeurodegenerative DisordersNeurogliaNeuronsParkinson DiseasePathogenicityPatientsPeripheralPharmacologyPlasmaPlayProcessProductionProtein IsoformsRag1 MouseResearchRoleSmall Interfering RNASpinal CordSubstantia nigra structureT cell responseT-Cell ActivationT-LymphocyteTdT-Mediated dUTP Nick End Labeling AssayTestingTissuesWestern Blottingalpha synucleinattenuationcalpain inhibitorchemokinecytokinedopaminergic neuronfunctional outcomesimprovedimproved outcomeinhibitor/antagonistknock-downmacrophagemigrationmouse modelneuron lossneuronal survivalnovel strategiesnovel therapeuticssurvival outcomesynuclein
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.
概括
帕金森病 (PD) 是一种使人衰弱的进行性退行性运动障碍,与丧失能力有关
黑质 (SN) 中的多巴胺能 (DA) 神经元以及 α-突触核蛋白 (α-syn) 的积累
大脑、小胶质细胞的激活、炎症细胞因子/趋化因子的产生、CD4+ T 细胞的浸润、
和神经退行性变。最有效的治疗方法是左旋多巴,但它不能阻止疾病进展,而且
渐进性质的机制尚不清楚。钙蛋白酶是一种受钙调节的半胱氨酸蛋白酶,在
在 PD 的 SN 和 SC(脊髓)变性中起关键作用,及其在 α-syn 聚集、激活
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和
疾病进展。虽然 calpain-1 裂解 α-syn 会促进 PD 样疾病中的突触核蛋白聚集,
两种主要钙蛋白酶异构体 calpain-1 和 calpain-2 精确参与 α-syn 呈递
CD4+ T 细胞仍然未知。初步研究在 MPTP 小鼠中鉴定出了 CD4+ T 细胞的一种亚型,
被钙蛋白酶抑制剂消除,表明钙蛋白酶和 CD4+ T 细胞的激活可能发挥作用
在 PD 的炎症过程和疾病进展中发挥关键作用。初步数据还表明
siRNA 介导的 calpain-2 敲低可减少人类 B 细胞的抗原呈递并抑制
CD4+ T 细胞的激活。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 反应性 CD4+ T 细胞亚型的扩增。我们还假设钙蛋白酶
抑制可能会减弱 α-syn 聚集和炎症 T 细胞的扩张,减少炎症和
支持神经元存活并改善 PD 患者的预后。提出了两个具体目标来测试
假设:(目标 1)研究 calpain-1 或 calpain-2 的激活是否与小胶质细胞相关
α-syn 呈递给 CD4+ T 细胞,导致 PD 样疾病进展和神经变性
小鼠疾病。 (目标 2)确定抑制 calpain-2 是否会减少小胶质细胞 α-syn 的呈递
和致病性 CD4+ T 细胞的产生,减轻 PD 小鼠模型的疾病进展。目标
本研究的目的是研究 calpain-1 和 calpain-2 在产生 α-syn 反应性致病性 CD4+ 中的作用
T 细胞,以及来自 MPTP 小鼠的 CD4+ T 细胞亚群是否可以诱导 PD 样疾病
免疫缺陷小鼠。计划进行研究以确定删除 calpain-1 是否会减弱 α-syn
使用 calpain-1 敲除 (KO) 小鼠进行 CD4+ T 细胞的聚集和扩增。此外,作用
calpain-2 抑制剂将在炎症 CD4+ T 细胞反应改变的研究中进行评估
calpain-1 KO 小鼠细胞因子/趋化因子的产生。测试不同钙蛋白酶亚型的影响
α-syn反应性致病性T细胞的产生和诱导神经元死亡和变性可能导致
开发治疗帕金森病和其他神经退行性疾病的新方法。
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)
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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:
8330422 - 财政年份:2012
- 资助金额:
$ 41.11万 - 项目类别:
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