Exploring astrocyte heterogeneity and plasticity: from phenotype to function

探索星形胶质细胞的异质性和可塑性:从表型到功能

基本信息

  • 批准号:
    RGPIN-2022-03849
  • 负责人:
  • 金额:
    $ 2.7万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2022
  • 资助国家:
    加拿大
  • 起止时间:
    2022-01-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

The diversity of astrocytes phenotypes and functions is baffling and often taken for granted when studying these cells. I will begin a Research Program designed to understand how this heterogeneity of astrocytes comes about and how it affects their function. My unique approach of applying techniques commonly used to study immune system development to a neural cell population will add an entirely novel and powerful approach to investigating this fundamental issue in neuroscience. Astrocytes are some of the most abundant cells of the CNS. Even though they have long been regarded as the "glue" of the brain, we now know that astrocytes play a multitude of roles in CNS development and homeostasis. This diversity in function infers that there might be more than one type of astrocyte. Indeed, over the last decade, it has become evident that astrocytes are a heterogeneous cell population with regard to their morphology and responses to changes in their environment (reactivity). Although this heterogeneity is clear, we do not know whether it is established during development, leading to pre-defined and committed astrocyte sub-lineages, or whether all astrocytes are derived from a limited pool of progenitors and their functional heterogeneity is defined by their local environment later in life. Similarly, we do not know whether astrocyte phenotypes and functions, such as reactivity, are fixed or plastic. Moreover, with regard to astrocyte reactive states, it is not known whether previously defined developmental and homeostatic functions of astrocytes depend on a specific reactive state. My research program aims to address these fundamental questions in glial cell biology. Using lineage tracing methods and combining these with state-of the art single cell analyses at both the RNA and the protein level, we will 1) establish whether the heterogeneity that we observe in astrocytes in adult mice is established during development, or later in life; 2) determine whether astrocytes that have become reactive in response to a specific stimulus are committed to this state, or are able revert to a different state; 3) determine whether specific astrocyte subtypes are associated with developmental and homeostatic functions. My Research Program will provide the first unbiased in-depth assessment of the development and function of astrocyte heterogeneity at the single cell level, and will provide us with a better understanding of the astrocyte landscape and its dynamics. I will apply my knowledge of glial cell biology, neuroimmunology and molecular biology, and leverage the exceptional expertise and technologies available within the Hotchkiss Brain Institute and the University of Calgary to answer these fundamental questions in neuroscience. Moreover, the interdisciplinary approach I apply will provide an excellent environment to train HQP in multiple fields, spanning neurodevelopment and cellular biology, as well as experimental tool development and implementation.
星形胶质细胞表型和功能的多样性令人困惑,在研究这些细胞时往往被视为理所当然。我将开始一项研究计划,旨在了解星形胶质细胞的这种异质性是如何产生的,以及它如何影响它们的功能。我将通常用于研究免疫系统发育的技术应用于神经细胞群体的独特方法将为研究神经科学中的这一基本问题增添一种全新而强大的方法。星形胶质细胞是CNS中最丰富的细胞之一。尽管它们长期以来被认为是大脑的“胶水”,但我们现在知道星形胶质细胞在CNS发育和稳态中发挥着多种作用。这种功能上的多样性意味着可能存在不止一种类型的星形胶质细胞。事实上,在过去的十年中,很明显,星形胶质细胞是一个异质细胞群体,就其形态和对环境变化的反应(反应性)而言。虽然这种异质性是明确的,但我们不知道它是否是在发育过程中建立的,导致预先定义和承诺的星形胶质细胞亚系,或者是否所有星形胶质细胞都来源于有限的祖细胞库,其功能异质性由其在生命后期的局部环境定义。同样,我们不知道星形胶质细胞的表型和功能,如反应性,是固定的还是可塑的。此外,关于星形胶质细胞的反应状态,目前还不知道是否以前定义的发育和稳态功能的星形胶质细胞依赖于一个特定的反应状态。我的研究计划旨在解决神经胶质细胞生物学中的这些基本问题。使用谱系追踪方法并将其与RNA和蛋白质水平的最新单细胞分析相结合,我们将1)确定我们在成年小鼠星形胶质细胞中观察到的异质性是在发育期间还是在生命后期建立的; 2)确定响应于特定刺激而变得反应性的星形胶质细胞是否被定型为这种状态,或者能够恢复到不同的状态; 3)确定特定的星形胶质细胞亚型是否与发育和稳态功能相关。我的研究计划将提供在单细胞水平上星形胶质细胞异质性的发展和功能的第一个公正的深入评估,并将为我们提供更好地了解星形胶质细胞景观及其动态。我将运用我在神经胶质细胞生物学、神经免疫学和分子生物学方面的知识,并利用霍奇基斯脑研究所和卡尔加里大学的特殊专业知识和技术来回答神经科学中的这些基本问题。此外,我所采用的跨学科方法将为在多个领域培训HQP提供良好的环境,包括神经发育和细胞生物学,以及实验工具的开发和实施。

项目成果

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Kuipers, Hedwich其他文献

Kuipers, Hedwich的其他文献

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{{ truncateString('Kuipers, Hedwich', 18)}}的其他基金

Exploring astrocyte heterogeneity and plasticity: from phenotype to function
探索星形胶质细胞的异质性和可塑性:从表型到功能
  • 批准号:
    DGECR-2022-00195
  • 财政年份:
    2022
  • 资助金额:
    $ 2.7万
  • 项目类别:
    Discovery Launch Supplement

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    2012
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Noradrenergic gating of astrocyte calcium-mediated homeostasis in vivo
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探索星形胶质细胞的异质性和可塑性:从表型到功能
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