INTRACELLULAR/EPIGENETIC MECHMS-NEUROTROPHIC PROPS OF ACTIVATED MICROGLIA

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 神经系统曾经被认为是“免疫特权”，与免疫系统活动隔离。 然而，大量证据表明，中枢神经系统（CNS）的正常发育和功能依赖于神经系统和免疫细胞之间的相互作用。 小胶质细胞是CNS的常驻免疫细胞，并对CNS环境的变化迅速作出反应。 小胶质细胞在神经元损伤后表现出吞噬活性。 活化的小神经胶质细胞产生神经毒性分子，包括炎性细胞因子、趋化因子、花生四烯酸、活性氧和氮物质以及生长抑制蛋白，如胡萝卜素（Kim和Vellis，2005; Lai和托德，2006）。相反，新出现的证据表明，给予特定的激活剂，小胶质细胞可以起到支持神经元存活、分化和潜在再生的作用。 体外和体内研究均表明，小胶质细胞产生神经营养因子，如神经生长因子（NGF）、神经营养因子3（NT 3）和脑源性神经营养因子（BDNF）（Kim和de Vellis，2005; Morgan等人，2004年）。另外的实验已经证明，神经元和小胶质细胞的共培养增加神经祖细胞中的神经发生（Walton等人，2006年）。 关于激活的小胶质细胞是否能够在受损的神经元中产生神经营养作用以及这些过程的信号传导和表观遗传机制知之甚少。 先前的实验表明，PI 3 K/AKT和MAPK通路可以作为潜在的信号传导机制，并且小胶质细胞信号传导通路的调节可能决定其神经营养或神经毒性表型。 为了研究神经元损伤的免疫反应中涉及的信号传导机制和基因调控，该提案提出了一种采用最先进技术的体外模型系统，该系统易于被本科研究生访问和使用。 增加我们对小胶质细胞中驱动神经营养性与神经毒性表型的机制的理解，将提供对CNS中免疫活性的内在神经保护作用的深入了解，并可能有助于开发在神经退行性疾病或损伤后再生期间促进这种活性的方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The nervous system was once considered to be "immune privileged" and isolated from immune system activity. However, a preponderance of evidence indicates that proper development and function of the central nervous system (CNS) relies on regulated interactions between nervous system and immune cells. Microglia are the resident immune cells of the CNS and respond rapidly to changes in the CNS environment. Microglia exhibit phagocytic activity following neuronal damage. Activated microglia produce neurotoxic molecules including inflammatory cytokines, chemokines, arachidonic acid, reactive oxygen and nitrogen species, and growth inhibiting proteins such as prostaglandins (Kim and Vellis, 2005; Lai and Todd, 2006). Conversely, emerging evidence suggests that, given specific activator(s), microglia may function to support neuronal survival, differentiation and potentially regeneration. Both in vitro and in vivo studies have shown that microglia produce neurotrophic factors such as nerve growth factor (NGF), neurotrophin 3 (NT3), and brain-derived neurotrophic factor (BDNF) (Kim and de Vellis, 2005; Morgan et al., 2004). Additional experiments have demonstrated that co-cultures of neurons and microglia increase neurogenesis in neural progenitor cells (Walton et al., 2006). Little is known about whether activated microglia are capable of producing neurotrophic effects in damaged neurons and which signaling and epigenetic mechanisms underlie these processes. Previous experiments have suggested that the PI3K/AKT and MAPK pathways could act as potential signaling mechanisms and it is likely that regulation of microglial signaling pathways determine their neurotrophic or neurotoxic phenotype. To investigate the signaling mechanisms and gene regulation involved in the immune response to neuronal damage, this proposal presents an in vitro model system employing state-of-the-art technology that is readily accessible to and utilized by undergraduate research students. Increasing our understanding of the mechanisms that drive neurotrophic verses neurotoxic phenotypes in microglia will provide insight into the intrinsic neuroprotective role of immune activity in the CNS and may aid in the development of methodologies to promote such activity during neurodegenerative disease or regeneration following injury.