INTRACELLULAR/EPIGENETIC MECHMS-NEUROTROPHIC PROPS OF ACTIVATED MICROGLIA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 神经系统曾被认为是“免疫特权”，不受免疫系统活动的影响。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调节相互作用。小胶质细胞是中枢神经系统的常驻免疫细胞，对中枢神经系统环境的变化反应迅速。小胶质细胞在神经元损伤后表现出吞噬活性。激活的小胶质细胞产生神经毒性分子，包括炎症细胞因子、趋化因子、花生四烯酸、反应氧和氮物种，以及生长抑制蛋白，如前列腺素(Kim和Vellis，2005；Lai和Todd，2006)。相反，新出现的证据表明，如果给予特定的激活剂(S)，小胶质细胞可能会支持神经元的生存、分化和潜在的再生。体外和体内研究表明，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(NT3)和脑源性神经营养因子(BDNF)(Kim和De Vellis，2005；Morgan等，2004)。其他实验表明，神经元和小胶质细胞共培养可增加神经前体细胞的神经发生(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效应，以及这些过程背后的信号和表观遗传机制，人们知之甚少。以前的实验表明，PI3K/AKT和MAPK通路可能是潜在的信号机制，小胶质细胞信号通路的调节可能决定了它们的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机制和基因调控，本提案提出了一个体外模型系统，该系统采用了最先进的技术，便于本科生使用和使用。增加我们对小胶质细胞神经营养和神经毒性表型驱动机制的了解，将有助于深入了解中枢神经系统免疫活性的内在神经保护作用，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.