Exploring the role of microbiota and inflammation in tic fluctuations

探索微生物群和炎症在抽动波动中的作用

基本信息

  • 批准号:
    10431544
  • 负责人:
  • 金额:
    $ 24.36万
  • 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:
    2022-05-01 至 2024-04-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT Chronic tic disorders (CTD), including Tourette’s disorder and persistent tic disorders, are a significant source of disability for children and adolescents, yet pharmacological therapies remain highly unsatisfactory due to serious adverse events. An ideal direction to develop safer treatments for CTD would be to target the same biological processes whereby tics spontaneously wax and wane over time; however, the mechanisms underlying these fluctuations remain poorly understood. A novel opportunity to solve this problem may come from recent evidence documenting that tic severity is influenced by the gut microbiota. Understanding whether changes in the composition of the gut microbiota may account for tic exacerbations - and through which molecular mechanisms - may lead to therapeutic breakthroughs in CTD; this issue, however, remains unexplored. The goal of the studies proposed in this R21 application is to explore whether and how variations in the gut microbiota contribute to tic exacerbations. The gut microbiota may influence tic severity through multiple mechanisms, including the synthesis of inflammatory cytokines. Ample correlational evidence points to tumor necrosis factor-α (TNF) as the inflammatory cytokine best associated with tic exacerbations. Thus, to test whether this cytokine increases tic severity, we evaluated its effects in a mouse model of CTD. These preliminary studies showed that low TNF doses that do not elicit sickness behavior significantly increase tic-like stereotypies in these mice. Based on these findings, we hypothesize that, in CTD patients, gut microbiota alterations lead to increased production of TNF or other inflammatory cytokines, which exacerbate tics. To test this hypothesis, the exploratory studies proposed in this R21 application will use a translational platform, combining clinical analyses in CTD patients and mechanistic experiments in mouse models. Specifically: - In Aim 1, we will assess the alterations of gut microbiota associated with CTD and test whether tic exacerbations are associated with alterations of the gut microbiota and inflammatory responses by testing fecal and blood samples from forty CTD patients and forty non-affected controls. - In Aim 2, we will test the causal link between gut microbiota alterations and tic exacerbations by transplanting fecal specimens from CTD-affected individuals into our mouse models of Tourette’s disorder; we will also test whether TNF or other inflammatory cytokines contribute to potential changes in tic severity. The translational studies proposed in this R21 application will be the first systematic analyses of the role of gut microbiota in tic fluctuations. If our hypothesis is verified, future R01-funded studies will test whether fecal material transplant from non-affected individuals and/or probiotic treatments can reduce tic severity. We will also study the downstream mechanisms whereby inflammation increases tic severity. Thus, our results may lead to the development of new, safer, mechanistically based treatments for CTD.
摘要

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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Marco Bortolato其他文献

Marco Bortolato的其他文献

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{{ truncateString('Marco Bortolato', 18)}}的其他基金

Mechanisms of information-processing and executive deficits caused by sleep deprivation
睡眠剥夺引起的信息处理和执行缺陷的机制
  • 批准号:
    10886925
  • 财政年份:
    2023
  • 资助金额:
    $ 24.36万
  • 项目类别:
Disentangling the biological links between violence and alcohol use
解开暴力和酗酒之间的生物学联系
  • 批准号:
    10660813
  • 财政年份:
    2023
  • 资助金额:
    $ 24.36万
  • 项目类别:
Exploring the role of neuroactive steroids in Tourette syndrome
探索神经活性类固醇在抽动秽语综合征中的作用
  • 批准号:
    10656348
  • 财政年份:
    2022
  • 资助金额:
    $ 24.36万
  • 项目类别:
Exploring the role of neuroactive steroids in Tourette syndrome
探索神经活性类固醇在抽动秽语综合征中的作用
  • 批准号:
    10464500
  • 财政年份:
    2022
  • 资助金额:
    $ 24.36万
  • 项目类别:
Exploring the role of microbiota and inflammation in tic fluctuations
探索微生物群和炎症在抽动波动中的作用
  • 批准号:
    10612010
  • 财政年份:
    2022
  • 资助金额:
    $ 24.36万
  • 项目类别:
Exploring the role of the protocadherin CELSR3 in Tourette syndrome
探索原钙粘蛋白 CELSR3 在抽动秽语综合征中的作用
  • 批准号:
    10532254
  • 财政年份:
    2021
  • 资助金额:
    $ 24.36万
  • 项目类别:
Exploring the role of the protocadherin CELSR3 in Tourette syndrome
探索原钙粘蛋白 CELSR3 在抽动秽语综合征中的作用
  • 批准号:
    10358988
  • 财政年份:
    2021
  • 资助金额:
    $ 24.36万
  • 项目类别:
Exploring steroid-based therapies to reduce opioid abuse
探索基于类固醇的疗法以减少阿片类药物滥用
  • 批准号:
    9916192
  • 财政年份:
    2020
  • 资助金额:
    $ 24.36万
  • 项目类别:
Deciphering gene-environment interactions in pathological reactive aggression
解读病理性反应性攻击中的基因-环境相互作用
  • 批准号:
    10460716
  • 财政年份:
    2014
  • 资助金额:
    $ 24.36万
  • 项目类别:
Deciphering gene-environment interactions in pathological reactive aggression
解读病理性反应性攻击中的基因-环境相互作用
  • 批准号:
    9116021
  • 财政年份:
    2014
  • 资助金额:
    $ 24.36万
  • 项目类别:

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Visuocortical Dynamics of Affect-Biased Attention in the Development of Adolescent Depression
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