INTRACELLULAR/EPIGENETIC MECHMS-NEUROTROPHIC PROPS OF ACTIVATED MICROGLIA

激活小胶质细胞的细胞内/表观遗传机制-神经营养支柱

基本信息

批准号：
8167511
负责人：
Annemarie Shibata
金额：
$ 3.53万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8167511
关键词：
Arachidonic Acids Arts Biological Models Brain-Derived Neurotrophic Factor Cells Coculture Techniques Computer Retrieval of Information on Scientific Projects Database Development Environment Epigenetic Process Exhibits Funding Gene Expression Regulation Grant Growth Immune Immune response Immune system In Vitro Inflammatory Injury Institution MAP Kinase Gene Methodology Microglia Natural regeneration Nerve Growth Factors Nervous system structure Neuraxis Neurodegenerative Disorders Neurons Neurotrophin 3 Nitrogen Oxygen PI3K/AKT Pathway interactions Phenotype Process Prostaglandins Proteins Regulation Research Research Personnel Resources Role Signal Pathway Signal Transduction Source Students Technology United States National Institutes of Health chemokine cytokine in vitro Model in vivo insight nerve stem cell neurogenesis neuronal survival neurotoxic neurotrophic factor research study

项目摘要

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.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目及研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。神经系统曾被认为具有“免疫特权”并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做出快速反应。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，包括炎性细胞因子、趋化因子、花生四烯酸、活性氧和氮以及前列腺素等生长抑制蛋白（Kim 和 Vellis，2005；Lai 和 Todd，2006）。相反，新出现的证据表明，给予特定的激活剂，小胶质细胞可能发挥支持神经元存活、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）、神经营养蛋白 3（NT3）和脑源性神经营养因子（BDNF）（Kim 和 de Vellis，2005；Morgan 等人，2005）。，2004）。其他实验表明，神经元和小胶质细胞的共培养可增加神经祖细胞的神经发生（Walton 等，2006）。关于激活的小胶质细胞是否能够在受损神经元中产生神经营养作用以及这些过程背后的信号传导和表观遗传机制，人们知之甚少。先前的实验表明，PI3K/AKT 和 MAPK 途径可以作为潜在的信号传导机制，并且小胶质细胞信号传导途径的调节很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，该提案提出了一种体外模型系统，采用最先进的技术，本科生可以轻松访问和使用该技术。增加我们对小胶质细胞中驱动神经营养表型与神经毒性表型的机制的了解，将有助于深入了解中枢神经系统中免疫活动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此类活动的方法。