Extra-nigral Neurodegeneration in Experimental Parkinson's Disease
实验性帕金森病的黑外神经变性
基本信息
- 批准号:8329678
- 负责人:
- 金额:$ 31.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-20 至 2014-08-31
- 项目状态:已结题
- 来源:
- 关键词:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine1-Methyl-4-phenylpyridiniumAcuteAffectAgeAnimal ModelAnimalsAntibodiesApoptosisApoptoticAstrocytesAttenuatedAutopsyAxonBehavioralBiochemicalBradykinesiaBrainBrain InjuriesC57BL/6 MouseCalciumCalpainCell DeathCell SurvivalCell membraneCell physiologyCellsCessation of lifeChronicDataDetectionDevelopmentDiseaseDisease ProgressionDopaEsthesiaEtiologyEventExperimental ModelsExperimental ParkinsonismExposure toFiberFunctional disorderGoalsHumanImmunofluorescence ImmunologicIn Situ Nick-End LabelingIn VitroInflammationInflammatoryInterferonsLabelLeadLevodopaMeasuresMediatingMembrane PotentialsMicrogliaMitochondriaModelingMonoamine Oxidase BMotor NeuronsMotor PathwaysMovementMovement DisordersMusMyelinNerve DegenerationNeurogliaNeuronsNeurotoxinsPTGS2 geneParkinson DiseaseParkinsonian DisordersPathogenesisPathologyPatientsPlayProcessRestRoleSJA6017SamplingSpinal CordStaining methodStainsSubstantia nigra structureSymptomsTechniquesTestingTherapeutic AgentsTimeTissuesToxinTremorUp-Regulationaxonal degenerationbasecalpain inhibitorcalpeptincell injurycell typecytochrome cfunctional restorationimproved functioningin vivoinsightmitochondrial dysfunctionmouse modelmyelin degenerationneurotoxicnew therapeutic targetnovel therapeuticspreventpublic health relevanceresponserestorationwhite matterwhite matter changewhite matter damage
项目摘要
Parkinson's disease (PD), a progressive degenerative movement disorder associated with loss of dopaminer-
gic neurons in substantia nigra (SN), leads to dysfunction. The current therapy, L-dopa, does not block dis-
ease progression; therefore, new therapies must be developed. Thus, the aim is to investigate inflammatory
events in brain and spinal cord (SC) and their degeneration in PD and characterize whether SC integrity and
neurons are lost in PD, contributing to dysfunction. Understanding the mechanisms of damage may help de-
velop new therapeutic strategies. While the etiology of PD is not fully understood, neurotoxins have been im-
plicated in PD pathogenesis. Toxic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been extensively
used as an experimental model. Since 1-methyl-4-phenylpyridinium ion (MPP+), the active toxic metabolite of
MPTP, increases intracellular-free Ca2+ level and promotes mitochondrial dysfunction, a Ca2+-mediated pathol-
ogy in PD has been hypothesized. Increased Ca2+ levels will promote calpain activation, increase inflamma-
tory responses, and damage brain/SC neurons, axons, and myelin, ultimately leading to functional deficit. Our
preliminary findings of direct detection of MPP+ in PD mouse SC, activation of astrocytes and microglia, and
increased calpain activity and expression in neurons indicate that SC is also affected. These findings were
corroborated by preliminary data showing motoneurons from SC of PD patients are also damaged. MPP+
treatment of ventral SC motor neuron cells (VSC4.1) showed increased intracellular [Ca2+] and calpain activity
with loss of membrane potential and death while calpain inhibitors (calpeptin, SJA6017) protected and restored
cell function. From these findings, we hypothesize that, since SC coordinates movement and sensation
of the body, damage to SC neurons, axons, and myelin, in addition to SN, may be an important factor
in PD, and calpain plays a crucial role in this dysfunction by promoting inflammation and cell death
and may be a target for therapy. Three specific aims will test the hypotheses. Specific Aim 1 will investigate
whether MPTP is directly converted into MPP+ in SC, enters through the degenerating axons from brain, or a
combination of both; examine the effects of MPTP (MPP+) on SN and SC neurons and white matter in acute
and chronic parkinsonism; assess calpain expression and activity and subsequent inflammation and cell
damage; and examine the status of neurons, axons, and myelin in SC of postmortem PD patients. Specific
Aim 2 will explore the effects of neurotoxic MPP+ in differentiated VSC4.1 cells and test the neuroprotective
efficacy of calpain inhibitors in vitro employing electrophysiological technique. Specific Aim 3 will examine
whether calpain inhibitor treatment will attenuate inflammation, prevent apoptosis of brain and SC neurons,
protect cells, preserve axons and myelin, and improve function in MPTP-induced PD mice. These studies will
delineate the role of calpain in inflammation and neurodegeneration in MPTP-induced PD and the probable
neuroprotective efficacy of calpain inhibitors in PD as therapeutic agents.
帕金森病 (PD) 是一种与多巴胺丧失相关的进行性退行性运动障碍
黑质 (SN) 的神经元会导致功能障碍。目前的治疗方法是左旋多巴,不能阻断疾病
缓解进展;因此,必须开发新的疗法。因此,目的是研究炎症
大脑和脊髓 (SC) 中的事件及其在 PD 中的退化,并表征 SC 的完整性和
PD 中神经元丢失,导致功能障碍。了解损害机制可能有助于解决
制定新的治疗策略。虽然帕金森病的病因尚不完全清楚,但神经毒素已成为人们关注的焦点。
与PD发病机制有关。有毒的1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)已被广泛
用作实验模型。由于 1-甲基-4-苯基吡啶鎓离子 (MPP+),其活性有毒代谢物
MPTP,增加细胞内游离 Ca2+ 水平并促进线粒体功能障碍,这是一种 Ca2+ 介导的病理过程
PD 中的ogy 已被假设。 Ca2+ 水平升高会促进钙蛋白酶激活,增加炎症-
反应,并损害大脑/SC 神经元、轴突和髓磷脂,最终导致功能缺陷。我们的
直接检测 PD 小鼠 SC 中 MPP+、星形胶质细胞和小胶质细胞活化的初步结果,以及
神经元中钙蛋白酶活性和表达的增加表明 SC 也受到影响。这些发现是
初步数据证实,PD 患者的 SC 运动神经元也受损。最大功率点+
腹侧 SC 运动神经元细胞 (VSC4.1) 的治疗显示细胞内 [Ca2+] 和钙蛋白酶活性增加
膜电位丧失并死亡,而钙蛋白酶抑制剂(calpeptin,SJA6017)则受到保护和恢复
细胞功能。根据这些发现,我们假设,由于 SC 协调运动和感觉
除了 SN 之外,SC 神经元、轴突和髓磷脂的损伤可能是一个重要因素
在帕金森病中,钙蛋白酶通过促进炎症和细胞死亡在这种功能障碍中发挥着至关重要的作用
并可能成为治疗的目标。三个具体目标将检验这些假设。具体目标 1 将进行调查
MPTP是否在SC中直接转化为MPP+,通过大脑退化轴突进入,还是通过
两者的结合;检查 MPTP (MPP+) 对急性期 SN 和 SC 神经元以及白质的影响
和慢性帕金森病;评估钙蛋白酶的表达和活性以及随后的炎症和细胞
损害;并检查PD患者死后SC中神经元、轴突和髓磷脂的状态。具体的
目标 2 将探讨神经毒性 MPP+ 对分化的 VSC4.1 细胞的影响并测试其神经保护作用
采用电生理技术体外钙蛋白酶抑制剂的功效。具体目标 3 将审查
钙蛋白酶抑制剂治疗是否会减轻炎症,防止大脑和 SC 神经元凋亡,
保护细胞,保留轴突和髓磷脂,并改善 MPTP 诱导的 PD 小鼠的功能。这些研究将
描述钙蛋白酶在 MPTP 诱导的 PD 炎症和神经变性中的作用以及可能的作用
钙蛋白酶抑制剂作为帕金森病治疗剂的神经保护功效。
项目成果
期刊论文数量(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:
$ 31.44万 - 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:
$ 31.44万 - 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:
10593090 - 财政年份:2022
- 资助金额:
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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
- 批准号:
10042307 - 财政年份:2020
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10731055 - 财政年份:2019
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10158428 - 财政年份:2019
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Attenuation of Inflammatory Response in Progressive Neurodegeneration in Parkinson's Disease
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9918754 - 财政年份:2019
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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:
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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
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10291814 - 财政年份:2012
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