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.
摘要
帕金森病(PD)是一种衰弱的进行性退行性运动障碍,与缺乏
黑质(SN)多巴胺能神经元与α-突触核蛋白(α-SYN)的积聚
大脑,小胶质细胞的激活,炎性细胞因子/趋化因子的产生,CD4+T细胞的渗透,
和神经退化。最有效的疗法L-多巴并不能阻止疾病的发展,而
其递进性机制尚不清楚。钙蛋白酶是一种受钙调节的半胱氨酸蛋白酶,它发挥着
在帕金森病脊髓变性中的关键作用及其在α-SYN聚集、活化中的作用
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
疾病的发展。虽然α-SYN的CalPain-1裂解促进了PD样疾病中的突触核蛋白聚集,
两个主要的Calain亚型,CalPain-1和CalPain-2,在α-SYN表达中的精确参与
CD4+T细胞仍不清楚。初步研究发现MPTP小鼠体内存在一种亚型的CD4+T细胞,
这一点被Calain抑制剂取消,表明Calain和CD4+T细胞的激活可能发挥了作用
在帕金森病的炎症过程和疾病进展中的关键作用。初步数据还表明,
SiRNA介导的Calain-2基因敲除减少人B细胞的抗原提呈并抑制
激活CD4+T细胞。因此,我们假设不同的钙蛋白亚型的激活可能有利于
帕金森病样疾病中α同源反应性T细胞亚型的扩增。我们还假设CalPain
抑制α-SYN可能减弱炎性T细胞的聚集和扩张,减轻炎症和
支持帕金森病患者的神经元存活和改善预后。提出了两个具体的目标来测试
假设:(目的1)研究calain-1或calain-2的激活是否与小胶质细胞有关
α-SYN递呈给CD4+T细胞导致帕金森病样疾病进展和神经变性
小鼠的疾病。(目的2)确定抑制Calain-2是否会减少α-SYN的小胶质细胞提呈
以及产生致病的CD4+T细胞,延缓帕金森病小鼠模型的疾病进展。目标是
本研究的目的是探讨CalPain-1和CalPain-2在α-SYN反应性致病细胞产生中的作用
T细胞,以及来自MPTP小鼠的CD4+T细胞亚群是否能在
免疫缺陷小鼠。计划进行研究以确定CalPain-1的缺失是否会减弱α-SYN
利用Calain-1基因敲除(KO)小鼠聚集和扩增CD4+T细胞。此外,还包括
Calain-2抑制剂将在炎性CD4+T细胞反应和炎性改变的研究中进行评估
Calain-1 KO小鼠细胞因子/趋化因子的产生测试不同的钙蛋白亚型在体内的作用
α-SYN反应性致病T细胞的产生和诱导神经元的死亡和变性可能导致
开发一种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)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
NAREN L BANIK其他文献
NAREN L BANIK的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Apoptosis assay to asses the anti-tumour effects of RP215 and GHR 106 monoclonal antibodies
通过细胞凋亡测定评估 RP215 和 GHR 106 单克隆抗体的抗肿瘤作用
- 批准号:
412165-2011 - 财政年份:2011
- 资助金额:
$ 41.11万 - 项目类别:
Experience Awards (previously Industrial Undergraduate Student Research Awards)
New Mexico Pregnancy Risk Asses Monitoring Sys, Maternal Child Hlth Epidemi......
新墨西哥州妊娠风险评估监测系统,母婴健康流行……
- 批准号:
7232729 - 财政年份:2006
- 资助金额:
$ 41.11万 - 项目类别:
New Mexico Pregnancy Risk Asses Monitoring Sys, Maternal Child Hlth Epidemi......
新墨西哥州妊娠风险评估监测系统,母婴健康流行……
- 批准号:
7406805 - 财政年份:2006
- 资助金额:
$ 41.11万 - 项目类别:
New Mexico Pregnancy Risk Asses Monitoring Sys, Maternal Child Hlth Epidemi......
新墨西哥州妊娠风险评估监测系统,母婴健康流行……
- 批准号:
7803588 - 财政年份:2006
- 资助金额:
$ 41.11万 - 项目类别:
Continuation of NC Pregnancy Risk Asses Monitoring Sys. Sys Collects Risk Fact...
北卡罗来纳州怀孕风险评估监测系统的延续。
- 批准号:
7807200 - 财政年份:2006
- 资助金额:
$ 41.11万 - 项目类别:
Continuation of NC Pregnancy Risk Asses Monitoring Sys. Sys Collects Risk Fact...
北卡罗来纳州怀孕风险评估监测系统的延续。
- 批准号:
7173492 - 财政年份:2006
- 资助金额:
$ 41.11万 - 项目类别:
Continuation of NC Pregnancy Risk Asses Monitoring Sys. Sys Collects Risk Fact...
北卡罗来纳州怀孕风险评估监测系统的延续。
- 批准号:
7226762 - 财政年份:2006
- 资助金额:
$ 41.11万 - 项目类别:
Continuation of NC Pregnancy Risk Asses Monitoring Sys. Sys Collects Risk Fact...
北卡罗来纳州怀孕风险评估监测系统的延续。
- 批准号:
7406806 - 财政年份:2006
- 资助金额:
$ 41.11万 - 项目类别:
New Mexico Pregnancy Risk Asses Monitoring Sys, Maternal Child Hlth Epidemi......
新墨西哥州妊娠风险评估监测系统,母婴健康流行……
- 批准号:
7173499 - 财政年份:2006
- 资助金额:
$ 41.11万 - 项目类别:
Collaborative: A Measurement Program in Sibera o Asses Disturbance-Driven Changes in Arctic Carbon Fluxes (RAISE)
协作:西伯利亚的测量计划 o 评估干扰驱动的北极碳通量变化 (RAISE)
- 批准号:
0451413 - 财政年份:2005
- 资助金额:
$ 41.11万 - 项目类别:
Standard Grant














{{item.name}}会员




