REGULATION OF GLIAL CELL DEVELOPMENT AND INJURY RESPONSE

众所周知，生长因子、神经营养因子、细胞因子和 激素调节神经胶质细胞的功能。表达上的变化 这些因素导致了细胞形态的严重变化和 中枢神经系统损伤和疾病过程中的分子表达数量 需要考虑的因素是压倒性的。我们选择将重点放在 那些我们认为对胶质细胞发育和 功能。肿瘤坏死因子-α(TNF-α)被认为与 许多中枢神经系统疾病的病因学。它被认为与这两起事件有关 生物体内的有益和细胞毒性作用：然而，几乎没有 已知的关于受体表达。我们提议的研究， 因此，将表达肿瘤坏死因子的细胞群(S)表型 中枢神经系统的受体。反应性星形胶质细胞和激活的小胶质细胞 是许多中枢神经系统疾病的特征。调节他们的行为的机制 人们对激活知之甚少。然而，我们实验室的研究 强调了两种细胞因子，睫状神经营养因子(CNTF)和 肿瘤坏死因子-α发挥着关键作用。因此，我们建议进一步 研究这些细胞因子在肿瘤早期阶段的作用。 炎症性疾病的过程。血小板衍生生长因子(PDGF-AA) 已知)可支持少突胶质细胞(OL)的存活和增殖。 活体数据显示，OL竞争有限的营养因子 并且该PDGF可以是确定 幸存下来的人。我们实验室最近的研究表明，只有 OL谱系早期的细胞表达PDGF-α(R)。这些 这些发现极其重要，因为它们揭示了主细胞 中枢神经系统中能够对PDGF-AA做出响应的群体是 OL：因此，提示PDGF-AA可能在糖尿病的治疗中发挥作用。 脱髓鞘障碍。我们建议通过提供以下内容来检验这一假设 实验性变态反应性脑脊髓炎(EAE)小鼠。给小鼠造成的 一种中枢神经系统炎症和脱髓鞘障碍。随着PDGF-AA的增长 因子处理。另一个已知可提高OL的增长因素 存活依赖神经营养因子-3(NT-3)。我们实验室的最新研究 支持细胞中存在具有生物学功能的TrkC受体 OL血统的一员。我们计划利用NORMAL、NT-3和TrkC基因敲除 用小鼠研究NT-3的潜在作用及其分子机制 在体内和体内对胶质细胞存活、增殖和凋亡的作用 体外培养。众所周知，中枢神经系统疾病由多种原因引起 侮辱往往表现出常见的伤害反应。这种重叠是 在许多与精神疾病相关的成人和儿童障碍中观察到 发育迟缓，艾滋病神经病变，缺血/缺氧，多发性硬化症，脑白质营养不良， 头部创伤、癫痫和脑炎。我们的目标将尝试 了解这些因素在CNS期间的复杂相互作用 发育、疾病和伤害反应。我们相信有些人 其中，这些因素在胶质形成和神经胶质恢复过程中是必不可少的； 而其他人在高表达时会起到有害的作用 中枢神经系统疾病期间的浓度。

It is well known that growth factors, neurotrophins, cytokines and hormones regulate glial cell function. Alterations in the expression of these factors results in serious changes in cell morphology and molecular expression during CNS injury and disease. The number of factors to be considered is overwhelming. We have chosen to focus on those that we consider to be imperative for glia development and function. Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the etiology of many CNS disorders. It is thought to be involved in both beneficial and cytotoxic actions within an organism: however, little is known with respect to receptor expression. Our proposed studies, therefore, will phenotype the cell population(s) that express TNF receptor in the CNS. Reactive astrocytes and activated microglia are hallmarks of many CNS disorders. The mechanisms that regulate their activation are poorly understood. however, studies in our laboratory have highlighted two cytokines, ciliary neurotrophic factor (CNTF) and TNF-alpha, as playing a pivotal role. We propose therefore, to further examine the involvement of these cytokines in the initial stages of the inflammatory disease process. Platelet-derived growth factor-AA (PDGF- AA) is known to support oligodendrocyte (OL) survival and proliferation. In vivo data suggests OL compete for a limited amount of trophic factor and that PDGF may be a rate limiting factor in determining the number of OL that survive. Recent studies in our laboratory have shown that only cells early within the OL lineage express the PDGF-alpha(r). These findings are extremely important because they reveal that the main cell population in the CNS that is capable of responding to PDGF-AA is the OL: therefore, suggesting a possible therapeutic role for PDGF-AA in demyelinating disorders. We propose to test this hypothesis by providing experimental allergic encephalomyelitis (EAE) mice. mice inflicted with a CNS inflammatory and demyelinating disorder. with PDGF-AA growth factor treatment. Another growth factor that is known to enhance OL survival is neurotrophin-3 (NT-3). Recent studies in our laboratory support the presence of a biologically functional TrkC receptor in cells of the OL lineage. We plan to utilize normal, NT-3 and TrkC knockout mice to determine the potential roles and molecular mechanisms of NT-3 action on glia survival, proliferation and apoptosis in vivo and in vitro. It is well known that CNS disorders resulting from a variety of insults often demonstrate common injury responses. This overlap is observed in many adult and pediatric disorders associated with mental retardation, AIDS neuropathy, ischemia/anoxia, MS, leukodystrophies, head trauma, epilepsy and encephalitis. Our goals will attempt to understand the complex interactions of these factors during CNS development, disease and the injury response. It is our belief that some of these factors are essential during gliogenesis and glial recovery; while others play a detrimental role when expressed at high concentrations during CNS disease.