Combining synucleinopathy and mitochondrial deficits in a novel mouse model of Parkinsons disease
在帕金森病的新型小鼠模型中结合突触核蛋白病和线粒体缺陷
基本信息
- 批准号:10531950
- 负责人:
- 金额:$ 43.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-15 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAnimal ModelAnimalsAutophagocytosisAutopsyBackBehavioralBilateralBrainBrain DiseasesCellsCharacteristicsClinical DataClinical TrialsCognitiveCognitive deficitsCorpus striatum structureDataDevelopmentDiseaseDisease modelDisease susceptibilityDopamineDopaminergic AgentsEffectivenessEtiologyExhibitsFailureFinancial HardshipFunctional disorderGaitGenesGeneticGoalsGoldHumanInjectionsLevodopaLocomotionMeasuresMissionMitochondriaModelingMolecularMolecular ProfilingMorbidity - disease rateMotorMusNational Institute of Neurological Disorders and StrokeNatureNerve DegenerationNeurodegenerative DisordersNeuronsParkinson DiseasePathogenesisPathogenicityPathologyPatientsPersonsPharmaceutical PreparationsPhasePhenotypePlayPresynaptic TerminalsProcessPublic HealthQuality of lifeRecombinantsReplacement TherapyResearchRoleSex DifferencesSideSubstantia nigra structureSystemTestingTimeToxinUnited States National Institutes of HealthValidationalpha synucleinaxonal degenerationdesigndopaminergic neurondrug discoveryexperimental studygastrointestinal functionhuman diseaseimprovedinnovationmitochondrial dysfunctionmotor behaviormotor deficitmotor disordermotor impairmentmouse modelneuroinflammationneuropathologynovelsocietal costssuccessful interventionsynucleinopathytherapeutic candidatetooltrait
项目摘要
The lack of animal models recreating the progressive pathology characteristic of Parkinson’s disease (PD) hinders the development of effective disease-modifying therapies. Thus, the goal of this project is to generate a new animal PD model that supports the development of such therapies. Clinical data revealed that axon terminal failure and “dying back” of dopaminergic neurons likely precede loss of substantia nigra cell bodies by many years in PD. This protracted process is not replicated in the acute toxin-induced animal models of PD, providing one possible explanation for the low predictive power of these models. The heterozygous deletion of the engrailed 1 gene in mice (En1+/–) results in axon terminal dysfunction and degeneration eventually leading to protracted loss of nigral dopaminergic neurons. This process causes striatal dopamine deficiency that leads to motor impairment. Furthermore, these changes are associated with mitochondrial deficits akin to those observed in some PD patients. Despite all the advantages that the En1+/– mouse model represents, it lacks α-syn aggregation. Thus, we hypothesize that mitochondrial deficits (due to heterozygous loss of En1) combined with bilateral injections of pathogenic α-syn fibrils (PFFs) will synergistically generate a highly relevant PD model – En1/SYN. We further predict that the En1/SYN model will exhibit a comprehensive set of PD-relevant behavioral deficits (both motor and non-motor) and will mimic PD neuropathology. This approach is innovative in combining, in mice, key aspects of PD, the susceptibility of the dopaminergic system, α-syn and the multifactorial nature of the etiology of PD. Supporting our hypothesis, our preliminary data show that PFFs-induced α-syn pathology is significantly exacerbated by the loss of En1. There are two major goals in this project: (1) We will trigger PFFs-induced α-syn pathology bilaterally by injecting pathogenic α-synuclein into both striata. By triggering the pathology on both sides of the brain the new mouse model is expected to induce robust motor, and more importantly cognitive deficits. We will bilaterally inject recombinant fibrillar α-syn (provided by Dr. Jiyan Ma), measure the development of α-syn-associated pathology, and then assess motor and non-motor function of mice at different time points; (2) We will validate the En1/SYN model as a model of PD, by comparing the features of our model to human PD in long-term experiments, as well as by testing if the gold-standard PD treatment L-DOPA reverses motor deficits induced by loss of nigral dopamine neurons and widespread α-syn aggregation. Our research is expected to generate a powerful tool, which can accelerate the development of symptomatic and/or disease-modifying therapies to treat motor and non-motor PD.
缺乏再现帕金森氏病(PD)进行性病理特征的动物模型阻碍了有效的疾病修饰疗法的发展。因此,该项目的目标是产生一种新的动物帕金森病模型,以支持此类疗法的开发。临床数据显示,帕金森病患者轴突终末衰竭和多巴胺能神经元“死亡”可能比黑质细胞体的丧失早许多年。这一旷日持久的过程在急性毒素诱导的帕金森病动物模型中没有复制,这为这些模型的低预测能力提供了一种可能的解释。小鼠Engraile1基因杂合性缺失(EN1+/-)导致轴突终末功能障碍和变性,最终导致黑质多巴胺能神经元的长期丢失。这一过程导致纹状体多巴胺缺乏,从而导致运动障碍。此外,这些变化与线粒体缺陷有关,类似于在一些PD患者中观察到的情况。尽管EN1+/-小鼠模型代表了所有的优点,但它缺乏α-SYN聚合。因此,我们假设线粒体缺陷(由于EN1杂合性丢失)与双侧致病性α-SYN纤维(PFF)注射相结合将协同产生高度相关的PD模型-EN1/SYN。我们进一步预测,EN1/SYN模型将表现出一系列与帕金森病相关的行为缺陷(运动和非运动),并将模拟帕金森病的神经病理。这一方法在小鼠中结合了帕金森病的关键方面、多巴胺能系统的易感性、α-SYN和帕金森病病因的多因素性质方面具有创新性。支持我们的假设,我们的初步数据显示,PFF诱导的α-SYN病理因EN1的丢失而显著加剧。这个项目有两个主要目标:(1)我们将通过在双侧纹状体注射致病的α-突触核蛋白来触发PFFS诱导的α-SYN病理。通过触发大脑两侧的病理,新的小鼠模型预计会导致强健的运动,更重要的是认知缺陷。我们将双侧注射重组纤维状α-SYN(马继炎博士提供),检测α-SYN相关病理的发展,然后评估不同时间点小鼠的运动和非运动功能;(2)我们将验证EN1/SYN模型是否为PD模型,方法是在长期实验中比较我们模型与人类PD模型的特点,以及测试金标准PD治疗L-多巴是否能逆转因黑质多巴胺神经元丢失和广泛的α-SYN聚集而导致的运动障碍。我们的研究有望产生一种强大的工具,可以加速对症和/或疾病修改疗法的发展,以治疗运动性和非运动性帕金森病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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专利数量(0)
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Jeffrey H Kordower其他文献
Gene Therapy for Parkinson’s Disease: Still a Hot Topic?
帕金森病的基因治疗:仍是热门话题吗?
- DOI:
10.1038/npp.2014.235 - 发表时间:
2014-12-08 - 期刊:
- 影响因子:7.100
- 作者:
Jeffrey H Kordower - 通讯作者:
Jeffrey H Kordower
Missing pieces in the Parkinson's disease puzzle
帕金森病拼图中缺失的部分
- DOI:
10.1038/nm.2165 - 发表时间:
2010-05-23 - 期刊:
- 影响因子:50.000
- 作者:
Jose A Obeso;Maria C Rodriguez-Oroz;Christopher G Goetz;Concepcion Marin;Jeffrey H Kordower;Manuel Rodriguez;Etienne C Hirsch;Matthew Farrer;Anthony H V Schapira;Glenda Halliday - 通讯作者:
Glenda Halliday
Lewy body pathology in long-term fetal nigral transplants: is parkinson's disease transmitted from one neural system to another?
长期胎儿黑质移植中的路易体病理:帕金森病是否从一个神经系统传播到另一个神经系统?
- DOI:
10.1038/npp.2008.161 - 发表时间:
2008-12-12 - 期刊:
- 影响因子:7.100
- 作者:
Jeffrey H Kordower;Patrik Brundin - 通讯作者:
Patrik Brundin
Jeffrey H Kordower的其他文献
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{{ truncateString('Jeffrey H Kordower', 18)}}的其他基金
Genetic Silencing of Striatal CaV1.3 Calcium Channels as a Potent Antidyskinetic Therapy for PD
纹状体 CaV1.3 钙通道的基因沉默作为 PD 的有效抗运动障碍疗法
- 批准号:
9975239 - 财政年份:2018
- 资助金额:
$ 43.61万 - 项目类别:
Genetic Silencing of Striatal CaV1.3 Calcium Channels as a Potent Antidyskinetic Therapy for PD
纹状体 CaV1.3 钙通道的基因沉默作为 PD 的有效抗运动障碍疗法
- 批准号:
10427300 - 财政年份:2018
- 资助金额:
$ 43.61万 - 项目类别:
Genetic Silencing of Striatal CaV1.3 Calcium Channels as a Potent Antidyskinetic Therapy for PD
纹状体 CaV1.3 钙通道的基因沉默作为 PD 的有效抗运动障碍疗法
- 批准号:
10179502 - 财政年份:2018
- 资助金额:
$ 43.61万 - 项目类别:
Does alpha synuclein strain or GCase enzyme activity drive clinical aggression in GBA-PD?
α 突触核蛋白菌株或 GCase 酶活性是否会导致 GBA-PD 患者的临床攻击行为?
- 批准号:
9789065 - 财政年份:2018
- 资助金额:
$ 43.61万 - 项目类别:
Genetic Silencing of Striatal CaV1.3 Calcium Channels as a Potent Antidyskinetic Therapy for PD
纹状体 CaV1.3 钙通道的基因沉默作为 PD 的有效抗运动障碍疗法
- 批准号:
9789969 - 财政年份:2018
- 资助金额:
$ 43.61万 - 项目类别:
Human Cell and Gene Therapy in Parkinsonian monkeys
帕金森猴的人类细胞和基因治疗
- 批准号:
8397422 - 财政年份:2012
- 资助金额:
$ 43.61万 - 项目类别:
Human Cell and Gene Therapy in Parkinsonian monkeys
帕金森猴的人类细胞和基因治疗
- 批准号:
8484898 - 财政年份:2012
- 资助金额:
$ 43.61万 - 项目类别:
Human Neural Stem Cells for HD: Technical and Empirical Advances
人类神经干细胞治疗 HD:技术和经验进展
- 批准号:
8095989 - 财政年份:2011
- 资助金额:
$ 43.61万 - 项目类别:
Human Neural Stem Cells for HD: Technical and Empirical Advances
人类神经干细胞治疗 HD:技术和经验进展
- 批准号:
8269640 - 财政年份:2011
- 资助金额:
$ 43.61万 - 项目类别:
TH and GTPCHI gene therapy for Parkinson's disease
TH 和 GTPCHI 基因治疗帕金森病
- 批准号:
7404386 - 财政年份:2007
- 资助金额:
$ 43.61万 - 项目类别:
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