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功能。表达改变 这些因素导致细胞形态的严重变化， CNS损伤和疾病中的分子表达。的数量 要考虑的因素是压倒性的。我们选择专注于 那些我们认为对神经胶质发育至关重要的基因， 功能肿瘤坏死因子-α（TNF-α）与 许多中枢神经系统疾病的病因。它被认为与这两种疾病有关 有益的和细胞毒性的作用：然而， 已知关于受体表达。我们提出的研究， 因此，将表达TNF的细胞群表型化 CNS中的受体。反应性星形胶质细胞和活化的小胶质细胞是 许多中枢神经系统疾病的标志。调节它们的机制 激活机制知之甚少。然而，我们实验室的研究 突出了两种细胞因子，睫状神经营养因子（CNTF）和 TNF-alpha在其中起着关键作用。因此，我们建议进一步 检查这些细胞因子在疾病的初始阶段的参与， 炎症性疾病过程。血小板衍生生长因子-AA（PDGF- AA）已知支持少突胶质细胞（OL）存活和增殖。 体内数据表明OL竞争有限量的营养因子 并且PDGF可能是确定肿瘤数量的速率限制因素， 生存下来的OL我们实验室最近的研究表明， OL谱系中的早期细胞表达PDGF-α（r）。这些 这些发现极其重要，因为它们揭示了主细胞 CNS中能够响应PDGF-AA的群体是 OL：因此，提示PDGF-AA可能在 脱髓鞘疾病我们建议通过提供以下信息来检验这一假设： 实验性变态反应性脑脊髓炎（EAE）小鼠。老鼠被 一种中枢神经系统炎症和脱髓鞘疾病。PDGF-AA生长 因子治疗。另一种已知的增强OL的生长因子 神经营养素-3（NT-3）。我们实验室最近的研究 支持细胞中存在生物功能性TrkC受体 OL血统。我们计划利用正常，NT-3和TrkC敲除 小鼠以确定NT-3的潜在作用和分子机制 在体内和体外对胶质细胞存活、增殖和凋亡的作用 体外众所周知，由多种疾病引起的CNS疾病是由多种疾病引起的。 侮辱通常表现出常见的伤害反应。该重叠 在许多与精神疾病相关的成人和儿童疾病中观察到 发育迟缓、AIDS神经病变、缺血/缺氧、MS、脑白质营养不良， 头部外伤癫痫和脑炎我们的目标是 了解这些因素在CNS过程中的复杂相互作用 发展，疾病和损伤反应。我们相信， 这些因子在胶质细胞的形成和恢复过程中起着重要作用; 而另一些则在高表达时起有害作用， CNS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.