Effect of agent and host factors on alpha-synuclein strain pathogenesis

病原体和宿主因素对α-突触核蛋白菌株发病机制的影响

基本信息

  • 批准号:
    10754428
  • 负责人:
  • 金额:
    $ 11.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-01-15 至 2026-12-31
  • 项目状态:
    未结题

项目摘要

Protein misfolding diseases, or proteinopathies, are a group of invariably fatal neurodegenerative disorders affecting more than 6.8 million Americans. In multiple system atrophy (MSA) and other synucleinopathy patients, the protein α-synuclein (α-syn) misfolds into a self-templating conformation that spreads via a prion- like manner throughout the body, including the central nervous system (CNS). It is hypothesized that the conformation, or strain, that α-syn misfolds into encodes information about the clinical symptoms and neuropathologies a patient will develop. While previous studies focused on the biochemical differences between α-syn strains, the mechanism of how those differences encode distinct biological phenotypes of disease is poorly understood. The long-term goal of our research is to identify the agent and host factors that contribute to the varied clinical presentations observed across synucleinopathies. In this proposal, we will test the hypothesis that strain-specific differences in aggregate transport and neuroanatomical spread contribute to disease pathogenesis. In Aim 1, we will use alexa fluor-labeled α-syn aggregates to investigate the rate and direction of axonal transport in vitro and in vivo. To determine the molecular mechanisms responsible for α-syn transport, we will use chemical and genetic tools to disrupt microtubule polymerization, dynein motor activity, and dynein cargo adaptor binding, and quantify the strain-specific effects on α-syn axonal transport. In Aim 2, we will determine the role of trans-synaptic spread on α-syn strain pathogenesis. To rigorously perform these studies, we will first determine the titer of three different α-syn strains both in vitro and in vivo. We will then use the sciatic nerve injection model, with and without nerve transection, to determine if α-syn neuroinvasion relies exclusively on trans-synaptic spread, of if extraneural pathways contribute to disease pathogenesis when the same titer of each strain is injected. Finally, we will perform a thorough disease pathogenesis study to establish a temporal-spatial map of strain-specific α-syn spread. This work is innovative because it is the first study to investigate how interactions between the host and strain impact disease progression, and to establish between in vitro and in vivo α-syn titers. This work is significant because it is the first to investigate how interactions between host and strain contribute to the mechanisms underlying axonal transport and trans-synaptic spread of disease. Critically, by identifying the cellular and molecular machinery responsible for α-syn propagation, the results of these experiments will lead to new areas of promising investigation.
蛋白质错误折叠疾病或蛋白质病是一组总是致命的神经退行性疾病 影响超过 680 万美国人。多系统萎缩 (MSA) 和其他突触核蛋白病 在患者体内,α-突触核蛋白(α-syn)错误折叠成一种自模板构象,通过朊病毒传播 以类似的方式遍布全身,包括中枢神经系统(CNS)。假设 α-syn 错误折叠成的构象或应变编码有关临床症状和 患者将出现的神经病理学。虽然之前的研究主要集中在生化差异上 在 α-syn 菌株之间,这些差异如何编码不同生物表型的机制 对疾病了解甚少。我们研究的长期目标是确定导致疾病发生的因素和宿主因素。 导致在突触核蛋白病中观察到的不同临床表现。在这个提案中,我们将测试 聚集体运输和神经解剖学传播中菌株特异性差异有助于的假设 疾病发病机制。在目标 1 中,我们将使用 Alexa 氟标记的 α-syn 聚集体来研究速率和 体外和体内轴突运输的方向。确定 α-syn 的分子机制 运输,我们将使用化学和遗传工具来破坏微管聚合、动力蛋白运动活动, 和动力蛋白货物接头结合,并量化对 α-syn 轴突运输的菌株特异性影响。在目标 2 中, 我们将确定跨突触传播对 α-syn 菌株发病机制的作用。为了严格执行这些 研究中,我们将首先在体外和体内测定三种不同α-syn菌株的滴度。然后我们将使用 坐骨神经注射模型,有或没有神经横断,以确定 α-syn 神经侵袭是否依赖 专门针对跨突触传播,当神经外途径是否有助于疾病发病机制时 注射相同滴度的每种菌株。最后,我们将进行彻底的疾病发病机制研究,以确定 菌株特异性 α-syn 扩散的时空图。这项工作具有创新性,因为它是第一项研究 研究宿主和菌株之间的相互作用如何影响疾病进展,并建立 体外和体内 α-syn 滴度。这项工作意义重大,因为它是第一个研究相互作用如何 宿主和菌株之间的相互作用有助于轴突运输和跨突触传播的机制 的疾病。至关重要的是,通过识别负责 α-syn 传播的细胞和分子机制, 这些实验的结果将带来有希望的研究新领域。

项目成果

期刊论文数量(1)
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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Amanda L. Woerman其他文献

Effect of host and strain factors on α-synuclein prion pathogenesis
宿主和毒株因素对α-突触核蛋白朊病毒发病机制的影响
  • DOI:
    10.1016/j.tins.2024.05.004
  • 发表时间:
    2024-07-01
  • 期刊:
  • 影响因子:
    15.100
  • 作者:
    Amanda L. Woerman;Jason C. Bartz
  • 通讯作者:
    Jason C. Bartz

Amanda L. Woerman的其他文献

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{{ truncateString('Amanda L. Woerman', 18)}}的其他基金

A Novel Gene Therapy Approach to Prevent Alpha-synuclein Misfolding in Multiple System Atrophy
一种防止多系统萎缩中α-突触核蛋白错误折叠的新基因治疗方法
  • 批准号:
    10673418
  • 财政年份:
    2023
  • 资助金额:
    $ 11.5万
  • 项目类别:
Effect of agent and host factors on alpha-synuclein strain pathogenesis
病原体和宿主因素对α-突触核蛋白菌株发病机制的影响
  • 批准号:
    10678036
  • 财政年份:
    2022
  • 资助金额:
    $ 11.5万
  • 项目类别:
Effect of agent and host factors on alpha-synuclein strain pathogenesis
病原体和宿主因素对α-突触核蛋白菌株发病机制的影响
  • 批准号:
    10375265
  • 财政年份:
    2022
  • 资助金额:
    $ 11.5万
  • 项目类别:
Effect of Agent and Host Factors on Alpha-Synuclein Strain Pathogenesis
试剂和宿主因素对 α-突触核蛋白菌株发病机制的影响
  • 批准号:
    10546484
  • 财政年份:
    2022
  • 资助金额:
    $ 11.5万
  • 项目类别:

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