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

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,还没有一种帕金森病(PD)的动物模型充分地将两者广泛结合起来

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 }}

Caryl E Sortwell其他文献

Caryl E Sortwell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('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:
American Society for Neural Therapy and Repair
美国神经治疗与修复学会
  • 批准号:
    7672655
  • 财政年份:
    2009
  • 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:
    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:
    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:
American Society for Neural Therapy and Repair
美国神经治疗与修复学会
  • 批准号:
    7114515
  • 财政年份:
    2006
  • 资助金额:
    $ 36.24万
  • 项目类别:

相似海外基金

Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
  • 批准号:
    495434
  • 财政年份:
    2023
  • 资助金额:
    $ 36.24万
  • 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
  • 批准号:
    10586596
  • 财政年份:
    2023
  • 资助金额:
    $ 36.24万
  • 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
  • 批准号:
    10590479
  • 财政年份:
    2023
  • 资助金额:
    $ 36.24万
  • 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
  • 批准号:
    10642519
  • 财政年份:
    2023
  • 资助金额:
    $ 36.24万
  • 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
  • 批准号:
    23K06011
  • 财政年份:
    2023
  • 资助金额:
    $ 36.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
  • 批准号:
    10682117
  • 财政年份:
    2023
  • 资助金额:
    $ 36.24万
  • 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
  • 批准号:
    10708517
  • 财政年份:
    2023
  • 资助金额:
    $ 36.24万
  • 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
  • 批准号:
    10575566
  • 财政年份:
    2023
  • 资助金额:
    $ 36.24万
  • 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
  • 批准号:
    23K15696
  • 财政年份:
    2023
  • 资助金额:
    $ 36.24万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
  • 批准号:
    23K15867
  • 财政年份:
    2023
  • 资助金额:
    $ 36.24万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了