Novel Modulators of TGFß1 signaling in regulation of remyelination by neural stem cells

TGFα1 信号传导在神经干细胞髓鞘再生调节中的新型调节剂

基本信息

  • 批准号:
    10544041
  • 负责人:
  • 金额:
    $ 38.21万
  • 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:
    2022-01-01 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT Loss of oligodendrocytes gives rise to demyelination, ultimately resulting in axonal degeneration and debilitating clinical outcomes in diseases like Multiple Sclerosis. While remyelination can prevent neurodegeneration, there are currently no approved therapies for promoting remyelination. Thus, there is an urgent need to identify factors that control remyelination. Neural stem cells in the adult subventricular zone are one of the sources of remyelinating oligodendrocytes. These cells are a heterogeneous population that show diverse responses to signaling pathways in the healthy vs demyelinated brain. We have studied one such pool marked by Gli1, which generates remyelinating oligodendrocytes only in response to demyelination. Our previous work showed that the recruitment and differentiation into oligodendrocytes leading to functional recovery is increased substantially by loss of Gli1 in this pool of neural stem cells; however the molecular mechanisms involved in this repair is not known. Through a transcriptomic analysis comparing gene expression in neural stem cells with and without Gli1 expression, we identified the TGFβ1 pathway as a major regulator of remyelination mediated by neural stem cells. However, the effects of TGFβ1 signaling are context dependent and differ with the cell-type, timing and dosage suggesting the presence of specific modulators of the pathway in different cells. Using a combination of bioinformatic analysis and remyelination studies in mice, we discovered a novel mediator of the TGFβ1 pathway, Gpnmb which is highly expressed along with its receptor CD44 in neural stem cells in response to demyelination. In the first aim, we will define the cell-autonomous function of Gpnmb in neural stem cells and its role in remyelination by neural stem cells. In the second aim, we will determine the impact of paracrine Gpnmb signaling through CD44 receptor on remyelination mediated by neural stem cells. In the third aim, we will elucidate the mechanisms of regulation of Gpnmb by TGFβ1 ligand and reciprocal modulation of the TGFβ1 pathway by Gpnmb. For the remyelination studies, we will use the toxin induced models of demyelination. To define the molecular mechanisms of the TGFβ1-Gpnmb signaling pathway, we will utilize in vitro neural stem cell cultures from adult mouse brain. Together, these studies will help identify therapeutic targets for promoting remyelination.
摘要 少突胶质细胞的损失引起脱髓鞘,最终导致轴突变性和衰弱。 多发性硬化症等疾病的临床结果。虽然髓鞘再生可以防止神经变性, 目前还没有批准的促进髓鞘再生的疗法。因此,迫切需要查明各种因素, 控制髓鞘再生成体室管膜下区的神经干细胞是神经干细胞的来源之一, 髓鞘再生少突胶质细胞这些细胞是一个异质群体,显示出不同的反应, 健康大脑和脱髓鞘大脑中的信号通路。我们已经研究了一个这样的池,标记为Gli 1, 产生再生髓鞘的少突胶质细胞只对脱髓鞘作出反应。我们以前的工作表明, 募集和分化为少突胶质细胞,导致功能恢复, 在这个神经干细胞库中Gli 1的丢失;然而,参与这种修复的分子机制并不 知道的通过转录组学分析比较有和没有Gli 1的神经干细胞中的基因表达 表达,我们确定了TGFβ1途径作为神经干细胞介导的髓鞘再生的主要调节因子。 细胞然而,TGFβ1信号传导的作用是环境依赖性的,并且随着细胞类型、时间和细胞周期的不同而不同。 剂量表明在不同细胞中存在该途径的特异性调节剂。结合使用 通过对小鼠的生物信息学分析和髓鞘再生研究,我们发现了TGFβ1通路的一种新介质, 在神经干细胞中响应脱髓鞘而沿着其受体CD 44高度表达的GPnmb。 在第一个目标中,我们将明确Gpnmb在神经干细胞中的细胞自主功能及其在神经干细胞中的作用。 神经干细胞的髓鞘再生在第二个目标中,我们将确定旁分泌Gpnmb信号传导的影响, 通过CD 44受体对神经干细胞介导的髓鞘再生的影响。在第三个目标中,我们将阐明 TGFβ1配体对Gpnmb的调节机制以及TGFβ1途径的相互调节 GPNMB。对于髓鞘再生研究,我们将使用毒素诱导的脱髓鞘模型。来定义 TGFβ1-Gpnmb信号通路的分子机制,我们将利用体外神经干细胞培养 成年老鼠的大脑。总之,这些研究将有助于确定促进髓鞘再生的治疗靶点。

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 }}

Jayshree Samanta其他文献

Jayshree Samanta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('Jayshree Samanta', 18)}}的其他基金

Novel Modulators of TGFß1 signaling in regulation of remyelination by neural stem cells
TGFα1 信号传导在神经干细胞髓鞘再生调节中的新型调节剂
  • 批准号:
    10366677
  • 财政年份:
    2022
  • 资助金额:
    $ 38.21万
  • 项目类别:
Role of GPNMB signaling in remyelination by oligodendrocyte progenitor cells
GPNMB 信号在少突胶质祖细胞髓鞘再生中的作用
  • 批准号:
    10431034
  • 财政年份:
    2022
  • 资助金额:
    $ 38.21万
  • 项目类别:
Role of GPNMB Signaling in Remyelination by Oligodendrocyte Progenitor Cells
GPNMB 信号在少突胶质祖细胞髓鞘再生中的作用
  • 批准号:
    10596170
  • 财政年份:
    2022
  • 资助金额:
    $ 38.21万
  • 项目类别:

相似海外基金

Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
  • 批准号:
    MR/Z503605/1
  • 财政年份:
    2024
  • 资助金额:
    $ 38.21万
  • 项目类别:
    Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
  • 批准号:
    2336167
  • 财政年份:
    2024
  • 资助金额:
    $ 38.21万
  • 项目类别:
    Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
  • 批准号:
    2402691
  • 财政年份:
    2024
  • 资助金额:
    $ 38.21万
  • 项目类别:
    Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
  • 批准号:
    2341428
  • 财政年份:
    2024
  • 资助金额:
    $ 38.21万
  • 项目类别:
    Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
  • 批准号:
    24K12150
  • 财政年份:
    2024
  • 资助金额:
    $ 38.21万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
  • 批准号:
    DE240100561
  • 财政年份:
    2024
  • 资助金额:
    $ 38.21万
  • 项目类别:
    Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
  • 批准号:
    2230829
  • 财政年份:
    2023
  • 资助金额:
    $ 38.21万
  • 项目类别:
    Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
  • 批准号:
    23K09542
  • 财政年份:
    2023
  • 资助金额:
    $ 38.21万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
  • 批准号:
    23K07552
  • 财政年份:
    2023
  • 资助金额:
    $ 38.21万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
  • 批准号:
    23K07559
  • 财政年份:
    2023
  • 资助金额:
    $ 38.21万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了