Biology of GFAP-expressing neural progenitors

描述（由申请人提供）：大量证据表明，新神经元的诞生（神经发生）在成人大脑的特定区域（包括人类）中持续终生。产生新神经元的成体神经祖细胞的生物学是相当感兴趣的，不仅反映了它们潜在的功能作用，而且反映了它们治疗或修复神经疾病或损伤的潜力。成年神经祖细胞的身份和起源是有争议的。实验证据表明，一些成年神经前体细胞表达胶质细胞酸性蛋白（GFAP），并表现出星形胶质细胞的某些特征。这些意见提出了一些问题和挑战。鉴于表达GFAP的星形胶质细胞在神经损伤、疾病和修复中的基本作用，重要的是要了解星形胶质细胞和成体神经祖细胞之间的关系。我们对表达GFAP的星形胶质细胞有着长期的兴趣，并开发了转基因小鼠模型来研究这些细胞在神经损伤和修复中的作用。在这里，我们应用这些模型来确定（i）GFAP表达细胞对体内和体外成体神经发生的相对贡献（如果有的话），（ii）是否所有GFAP表达神经胶质细胞都具有神经发生潜力，或者这种潜力是否与表现出不同表型特征的细胞亚群相关，以及（iii）调节GFAP表达神经祖细胞神经发生潜力的因素，特别是在脑损伤之后。为此，我们使用体外和体内技术以及几种转基因小鼠模型，其允许（a）GFAP表达细胞的消融，（B）GFAP表达细胞后代的谱系分析和命运作图，以及（c）特异性地从GFAP表达细胞中删除基因。我们的前期工作和初步数据与以下几个假设相一致：（1）成人前脑中主要的神经前体细胞表达GFAP：（2）并非所有表达GFAP的胶质细胞都具有神经发生潜能，神经发生潜能与表达GFAP的细胞的存在相关，这些细胞表现出与放射状胶质细胞相似的某些表型特征;（3）表达GFAP的祖细胞的多能潜力可以通过环境条件来操纵。从这里提出的研究结果将有助于建立成人神经祖细胞的身份和调节的基本信息，并对定义神经祖细胞和星形胶质细胞之间的关系，对损伤和疾病的反应。了解GFAP表达神经祖细胞的生物学及其与星形胶质细胞的关系，星形胶质细胞在整个中枢神经系统中广泛存在，可能会揭示改善损伤或疾病后神经修复的新研究途径。

DESCRIPTION (provided by applicant): Substantial evidence indicates that the birth of new neurons (neurogenesis) continues throughout life in specific regions of the adult brain, including humans. The biology of the adult neural progenitors that give rise to new neurons is of considerable interest reflecting not only their potential functional roles, but also their potential for treatment or repair of neurological illness or injury. The identity and origin of adult neural progenitors are controversial. Experimental evidence suggests that some adult neural progenitors express glial fibrillary acidic protein (GFAP) and exhibit certain characteristics of astroglia. These observations raise questions and challenges. Given the fundamental roles of GFAP expressing astroglia in neural injury, disease and repair, it is important to understand the relationships, if any, between astroglia and adult neural progenitors. We have a longstanding interest in GFAP-expressing astroglia, and have developed transgenic mouse models to study these cells in neural injury and repair. Here, we apply these models to determine (i) the relative contribution, if any, of GFAP-expressing cells to adult neurogenesis in vivo and in vitro, (ii) whether all GFAP-expressing glia have neurogenic potential or whether this potential is associated with a subpopulation of cells that exhibits distinct phenotypic characteristics, and (iii) factors that regulate the neurogenic potential of GFAP-expressing neural progenitors, in particular after brain injury. To do so we use in vitro and in vivo techniques and several transgenic mouse models that allow (a) ablation of GFAP-expressing cells, (b) lineage analysis and fate mapping of progeny of GFAP-expressing cells, and (c) deletion of genes specifically from GFAP-expressing cells. Our preparatory work and preliminary data are consistent with several hypotheses including: (1) the predominant neural progenitors in adult forebrain express GFAP; (2) not all GFAP-expressing glia have neurogenic potential, neurogenic potential correlates with the presence of GFAP-expressing cells that exhibit certain phenotypic characteristics similar to radial glia; (3) the multipotent potential of GFAP-expressing progenitors can be manipulated by environmental conditions. Findings from studies proposed here will contribute fundamental information towards establishing the identity and regulation of adult neural progenitor cells, and towards defining the relationships between neural progenitors and the astroglia that respond to injury and disease. Understanding the biology of GFAP-expressing neural progenitors and their relationship to astroglia, which are widespread throughout the central nervous system, may reveal novel research avenues towards improving neural repair after injury or disease.