Exploring astrocyte heterogeneity and plasticity: from phenotype to function

星形胶质细胞表型和功能的多样性令人费解，在研究这些细胞时往往被认为是理所当然的。我将开始一个研究项目，旨在了解星形胶质细胞的异质性是如何产生的，以及它是如何影响它们的功能的。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加一种全新而强大的方法。星形胶质细胞是中枢神经系统中含量最丰富的细胞之一。尽管长期以来，星形胶质细胞一直被认为是大脑的“粘合剂”，但我们现在知道，星形胶质细胞在中枢神经系统的发育和动态平衡中扮演着多种角色。这种功能上的多样性推断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，星形胶质细胞在形态和对环境变化(反应性)的反应方面是一个异质细胞群体，这一点已经变得很明显。虽然这种异质性很明显，但我们不知道这种异质性是在发育过程中建立的，导致了预先定义和承诺的星形胶质细胞亚系，还是所有的星形胶质细胞都是从有限的祖细胞池中衍生出来的，它们的功能异质性是由他们生命后期的局部环境决定的。同样，我们不知道星形胶质细胞的表型和功能，如反应性，是固定的还是可塑性的。此外，关于星形胶质细胞的反应状态，还不知道之前定义的星形胶质细胞的发育和稳态功能是否依赖于特定的反应状态。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这些方法与最先进的单细胞RNA和蛋白质水平分析相结合，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过程中建立的，还是在生命的后期建立；2)确定对特定刺激产生反应的星形胶质细胞是否致力于这种状态，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动态平衡功能相关。我的研究计划将首次在单细胞水平上对星形胶质细胞异质性的发展和功能进行无偏见的深入评估，并将使我们更好地了解星形胶质细胞的景观及其动力学。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提供的卓越专业知识和技术来回答神经科学中的这些基本问题。此外，我采用的跨学科方法将提供一个极好的环境，在多个领域培训HQP，包括神经发育和细胞生物学，以及实验工具的开发和实施。

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.