Biology of GFAP-expressing neural progenitors

描述(申请人提供)：大量证据表明，在成人大脑的特定区域，包括人类，新神经元的诞生(神经发生)贯穿整个生命。能产生新神经元的成体神经前体细胞的生物学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。成体神经前体细胞的身份和起源存在争议。实验证据表明，一些成年神经前体细胞表达胶质纤维酸性蛋白(GFAP)，并表现出星形胶质细胞的某些特征。这些观察结果提出了问题和挑战。鉴于GFAP表达星形胶质细胞在神经损伤、疾病和修复中的基础作用，了解星形胶质细胞和成年神经前体细胞之间的关系是很重要的。长期以来，我们一直对表达GFAP的星形胶质细胞感兴趣，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)表达GFAP的细胞在体内和体外对成人神经发生的相对贡献，(Ii)是否所有表达GFAP的神经胶质细胞都具有神经生成潜力，或者这种潜力是否与表现出不同表型特征的细胞亚群有关，以及(Iii)调节表达GFAP的神经前体细胞的神经生成潜力的因素，特别是在脑损伤后。为此，我们使用了体外和体内技术以及几种转基因小鼠模型，这些模型允许(A)去除表达GFAP的细胞，(B)对表达GFAP的细胞的后代进行谱系分析和命运定位，以及(C)从表达GFAP的细胞中删除特定的基因。我们的前期工作和初步数据与以下几个假设是一致的：(1)成人前脑中主要的神经前体细胞表达GFAP；(2)并不是所有表达GFAP的神经胶质细胞都具有神经生成潜力，神经生成潜力与表达GFAP的细胞的存在有关，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的前体细胞的多潜能可以受到环境条件的调控。本文提出的研究结果将有助于确定成年神经前体细胞的身份和调控，以及确定神经前体细胞和星形胶质细胞之间的关系，这些神经前体细胞对损伤和疾病做出反应。了解表达GFAP的神经前体细胞的生物学及其与星形胶质细胞的关系，可能会为改善损伤或疾病后的神经修复提供新的研究途径。

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.