ASTROCYTE DIVERSITY AND CNS AXONAL GROWTH

星形胶质细胞多样性和中枢神经系统轴突生长

基本信息

批准号：
2265591
负责人：
ROBERT H. MILLER
金额：
$ 17.44万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-02-01 至 1997-01-31
项目状态：
已结题

项目摘要

Astrocytes of the vertebrate CNS have been proposed to perform a wide variety of different functions including acting as a substrate for axon growth during development, contributing to the induction of the blood brain barrier and forming glial scars following injury to the adult CNS. Our recent studies suggest that astrocytes are a heterogeneous class of cells. In the proposed studies we will examine astrocyte diversity in the rat spinal cord and test the hypothesis that distinct types of astrocytes perform distinct functions in the developing, adult and injured spinal cord. Three different approaches will be used to define astrocyte diversity in the developing spinal cord: single cell cloning, retrovirus mediated gene transfer and the generation of cell type specific monoclonal antibodies. Initial studies suggest that cultures of neonatal rat spinal cord contains five morphologically distinct types of astrocytes. We will determine the time of origin, and the factors, that regulate proliferation and differentiation of each of these different cell types. Retrovirus mediated gene transfer will be used to determine the cell lineage relationships of the different types of astrocytes, both in cultures containing all classes of spinal cord cells and in the intact developing spinal cord. Recently isolated, as well as novel cell-type specific monoclonal antibodies will be used to distinguish biochemical differences between these cell types and to localize them in the intact spinal cord. The functional potential of the different types of astrocytes will be examined by analyzing their ability to support neurite outgrowth from developing neurons, suppress glial scar formation and reestablish the blood brain barrier after injury in the adult. The extent of neurite outgrowth and its molecular basis on the different populations of astrocytes will be established using purified cell populations in vitro. Transplantation of nitrocellulose implants coated with the different populations of astrocytes in to the adult CNS will be used to assess the ability of each type of cell to suppress glial scar formation and re-establish the blood brain barrier after injury. These studies will provide new, and important information on the extent and functional significance of astrocyte diversity in the spinal cord. Since the response of astrocytes to CNS injury is important for functional recovery it is critical to define specific astrocytic cell types in the CNS and to describe their individual functions following a CNS lesion. Such information is essential if we are to understand and subsequently manipulate the complex astrocytic response to CNS injury.

已经提出了脊椎动物中枢神经系统的星形胶质细胞进行宽多种不同功能，包括充当轴突的底物发育过程中的增长，有助于诱导血液成年中枢神经系统受伤后的脑屏障和形成神经胶质疤痕。我们最近的研究表明，星形胶质细胞是异质类细胞。在拟议的研究中，我们将检查星形胶质细胞的多样性大鼠脊髓并检验以下假设星形胶质细胞在发展中，成人和受伤的脊髓。将使用三种不同的方法来定义星形胶质细胞多样性发育中的脊髓：单细胞克隆，逆转录病毒介导的基因转移和细胞类型特异性单克隆抗体的产生。初步研究表明新生大鼠脊髓的培养物包含五种形态上不同类型的星形胶质细胞。我们将确定原籍时间和调节的因素这些不同细胞类型的每一种的增殖和分化。逆转录病毒介导的基因转移将用于确定细胞不同类型的星形胶质细胞的谱系关系，都在包含所有类别的脊髓细胞及完整的培养物发展脊髓。最近孤立以及新颖的细胞类型特定的单克隆抗体将用于区分生化这些细胞类型之间的差异并将它们定位在完整中脊髓。不同类型的星形胶质细胞的功能潜力将是通过分析其支持神经突生长的能力来检查发展神经元，抑制神经胶质疤痕形成并重新建立成人受伤后的血脑屏障。神经突的程度生长及其在不同种群的分子基础星形胶质细胞将在体外使用纯化的细胞种群建立。涂有不同的硝酸纤维素植入物的移植成人中枢神经系统中的星形胶质细胞种群将用于评估每种类型的细胞抑制神经胶质疤痕形成的能力和受伤后重新建立血脑屏障。这些研究将在范围内提供新的和重要的信息星形胶质细胞多样性在脊髓中的功能意义。由于星形胶质细胞对中枢神经系统损伤的反应对于功能恢复至关重要的是定义特定的星形细胞细胞中枢神经系统中的类型并描述其单个功能之后中枢神经系统病变。如果我们要理解和随后，操纵对中枢神经系统损伤的复杂星形胶质性反应。