The Rat Pre-Formed Alpha-Synuclein Fibril Model of Parkinson's Disease
帕金森病大鼠预制α-突触核蛋白原纤维模型
基本信息
- 批准号:9751424
- 负责人:
- 金额:$ 36.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-01 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:Amygdaloid structureAnimal ModelAreaBehaviorBilateralBiological ModelsBloodBody SizeClinicalCorpus striatum structureDataDenervationDevelopmentDiagnosisDiseaseDisease modelDopamineDrug KineticsEndopeptidase KExhibitsFemaleGeneticHumanImpairmentInjectionsInterventionIpsilateralLevodopaLewy BodiesLightMeasurableMemory impairmentModelingMonitorMotorMusNerve DegenerationParkinson DiseasePathologicPathologyPatientsPerformancePeripheralPhasePositron-Emission TomographyProteinsRattusReportingResistanceSeedsSubstantia nigra structureSynapsesTestingThioflavin STimeTyrosine 3-MonooxygenaseUbiquitinValidationalpha synucleinbrain sizeclinical predictorsclinical translationdopamine transporterdopaminergic neurongender differencein vivoin vivo imagingmalemotor deficitmotor impairmentmotor symptomnerve supplynon-drugnovelpars compactapharmacodynamic biomarkerpre-clinicalsample collectionsynucleinopathytreatment strategyvalidation studiesvesicular monoamine transporter
项目摘要
Until recently no animal model of Parkinson’s disease (PD) has adequately incorporated both widespread
alpha-synuclein (α-syn) pathology and protracted significant nigrostriatal degeneration. In 2012 Luk and
colleagues described how intrastriatal injection of synthetic α-syn preformed fibrils (PFFs) into wildtype (WT)
mice seeded endogenous accumulation of Lewy Body (LB)-like intracellular α-syn inclusions and ultimate
nigrostriatal degeneration. In light of the fact that the rat model system offers distinct advantages over mice
(fine motor behaviors, greater synaptic complexity, genetics and pharmacokinetics more similar to humans,
larger brain and body size more amenable to neurosurgical interventions and sample collection), we recently
characterized the results of unilateral injection of mouse α-syn PFFs into the striatum of rats. Similar to the
mouse, we observed phosphorylated α-syn intraneuronal accumulations in several areas that innervate the
striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars
compacta (SNpc). α-Syn accumulations co-localized with ubiquitin, p62, and were thioflavin-S-positive and
proteinase-k resistant. Although α-syn inclusions within the SNpc remained ipsilateral to striatal injection, we
observed bilateral reductions in nigral dopamine neurons 6 months following α-syn PFF injection. Further, PFF
injected rats exhibited reductions in striatal dopaminergic innervation as well as deficits in striatal dopamine
and metabolites. This initial study demonstrates that α-syn PFFs are sufficient to seed the pathological
conversion and propagation of endogenous α-syn to induce a progressive, neurodegenerative model of α-
synucleinopathy in rats. In the present IGNITE application we seek to identify which α-syn species (human,
mouse, rat) results in consistent loss of 60% nigral dopamine neurons over the course of 4 months after
intrastriatal injection into rats (Aim 1). Once identified, we will conduct internal validation studies to
systematically characterize the time course and magnitude of α-syn pathology, striatal dopamine and
metabolite loss, levels of striatal dopaminergic innervation (tyrosine hydroxylase, vesicular monoamine
transporter, and dopamine transporter) and deficits in motor behaviors (Aim 2). Lastly, we will conduct PD-relevant
external validation studies including: 1) investigating whether PFF-induced motor deficits are
reversible with levodopa and 2) conduct non-invasive longitudinal in vivo imaging of nigrostriatal DA synthesis,
storage and turnover using positron emission tomography (PET) (Aim 3). We propose that optimization,
internal validation and external validation studies in the progressive rat α-syn PFF PD model will allow for
direct comparison to clinical metrics in PD patients and facilitate the development of novel disease modifying
therapies.
直到最近,还没有帕金森病(PD)的动物模型充分地结合了广泛的
α-突触核蛋白(α-syn)病理学和持久的显著黑质纹状体变性。在2012年,
他的同事描述了纹状体内注射合成的α-syn预形成的纤维(PFF)如何进入野生型(WT)
小鼠接种路易体(LB)样细胞内α-syn包涵体的内源性积累,
黑质纹状体变性鉴于大鼠模型系统相对于小鼠具有明显的优势,
(fine运动行为,更大的突触复杂性,遗传学和药代动力学更类似于人类,
更大的大脑和身体尺寸更适合神经外科干预和样本收集),我们最近
表征了将小鼠α-syn PFF单侧注射到大鼠纹状体中的结果。类似于
小鼠,我们观察到磷酸化的α-syn神经元内的积累在几个领域,支配
纹状体,最显著的是额叶和岛叶皮质,杏仁核和黑质部
(SNPC).α-Syn积聚与泛素、p62共定位,并且是硫磺素-S阳性,
蛋白酶-K抗性。尽管SNpc中的α-syn包涵体仍然与纹状体注射同侧,我们
在α-syn PFF注射后6个月观察到黑质多巴胺神经元的双侧减少。此外,PFF
注射的大鼠表现出纹状体多巴胺能神经支配减少以及纹状体多巴胺
和代谢物。这项初步研究表明,α-syn PFF足以接种病理性
内源性α-syn的转化和增殖,以诱导α-syn的进行性神经退行性模型。
大鼠的突触核蛋白病。在本IGNITE申请中,我们试图识别哪些α-syn物种(人类,
小鼠,大鼠)在4个月的过程中导致60%的黑质多巴胺神经元的一致损失,
大鼠纹状体内注射(目的1)。一旦确定,我们将进行内部验证研究,
系统地表征α-syn病理学、纹状体多巴胺和
代谢物损失,纹状体多巴胺能神经支配(酪氨酸羟化酶,囊泡单胺
转运蛋白和多巴胺转运蛋白)和运动行为缺陷(目标2)。最后,我们将进行PD相关
外部验证研究包括:1)调查PFF诱导的运动缺陷是否
左旋多巴可逆和2)进行黑质纹状体DA合成的非侵入性纵向体内成像,
储存和周转使用正电子发射断层扫描(PET)(目标3)。我们建议优化,
进行性大鼠α-syn PFF PD模型的内部验证和外部验证研究将允许
直接与PD患者的临床指标进行比较,并促进新疾病修饰的开发
治疗
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)
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Caryl E Sortwell其他文献
Caryl E Sortwell的其他文献
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{{ truncateString('Caryl E Sortwell', 18)}}的其他基金
STN DBS Effects on Neuroinflammation and Degeneration Induced by Alpha-Synuclein Inclusions
STN DBS 对 α-突触核蛋白包涵体诱导的神经炎症和变性的影响
- 批准号:
10355915 - 财政年份:2021
- 资助金额:
$ 36.24万 - 项目类别:
The Rat Pre-Formed Alpha-Synuclein Fibril Model of Parkinson's Disease
帕金森病大鼠预制α-突触核蛋白原纤维模型
- 批准号:
9387180 - 财政年份:2017
- 资助金额:
$ 36.24万 - 项目类别:
American Society for Neural Therapy and Repair/International Conference on Neural
美国神经治疗与修复学会/国际神经会议
- 批准号:
8129235 - 财政年份:2011
- 资助金额:
$ 36.24万 - 项目类别:
Pleiotrophin Overexpression to Facilitate Repair and Graft Efficacy in Parkinsoni
多效蛋白过度表达促进帕金森病的修复和移植功效
- 批准号:
7799276 - 财政年份:2007
- 资助金额:
$ 36.24万 - 项目类别:
Pleiotrophin Overexpression to Facilitate Repair and Graft Efficacy in Parkinsoni
多效蛋白过度表达促进帕金森病的修复和移植功效
- 批准号:
7447803 - 财政年份:2007
- 资助金额:
$ 36.24万 - 项目类别:
Pleiotrophin Overexpression to Facilitate Repair and Graft Efficacy in Parkinsoni
多效蛋白过度表达促进帕金森病的修复和移植功效
- 批准号:
7246907 - 财政年份:2007
- 资助金额:
$ 36.24万 - 项目类别:
Pleiotrophin Overexpression to Facilitate Repair and Graft Efficacy in Parkinsoni
多效蛋白过度表达促进帕金森病的修复和移植功效
- 批准号:
8070414 - 财政年份:2007
- 资助金额:
$ 36.24万 - 项目类别:
Pleiotrophin Overexpression to Facilitate Repair and Graft Efficacy in Parkinsoni
多效蛋白过度表达促进帕金森病的修复和移植功效
- 批准号:
7591042 - 财政年份:2007
- 资助金额:
$ 36.24万 - 项目类别:
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