Signaling events regulating microglial functions and activation phenotypes

小胶质细胞是大脑的免疫细胞，它们保护大脑免受病原体的侵袭。此外，小胶质细胞的吞噬活性、细胞因子的产生和营养因子的分泌调节神经元的可塑性，这是允许大脑重组其神经连接以应对新情况的关键现象。虽然调节的小胶质细胞活动是有益的，但调节失调的小胶质细胞活动会导致神经元功能障碍，并促进认知障碍和神经元死亡。小胶质细胞的这些相反作用是可行的，因为它们的不同功能归因于特定的激活表型。*我研究的长期目标是揭示小胶质细胞在病原体清除、旁观者神经元损伤、突触维持和神经元可塑性中作用的分子机制。这一洞察将使我们能够探索小胶质细胞在包括学习、记忆和认知在内的高级大脑功能中的作用。为了解决我的长期目标，我建议利用聚(ADP-核糖)聚合酶-1(PARP-1)作为揭示小胶质细胞信号事件的其他方面的成熟工具，探索以下短期(5年)目标。*1)确定PARP-1在小胶质细胞激活表型转换调节中的作用。*2)确定与小胶质细胞激活表型转换相关的转录因子。*3)剖析小胶质细胞吞噬类型的分子基础。*拟议的研究将在体外进行，一些关键点将在体内得到证实。我们将使用我最近创建的小胶质细胞靶向分子工具来操纵PARP-1的表达和活性，PARP-1被认为是小胶质细胞功能的关键调节因子。小胶质细胞PARP-1激活可促进促炎反应和失控的神经元吞噬作用。小胶质细胞PARP-1抑制抑制免疫反应，同时仍能消除病原体。*这项拟议计划的结果将提供有关小胶质细胞功能调节的详细机制信息，从病原体消除到神经元突触重构。这些信息将很容易被纳入神经免疫学和突触可塑性领域，但也对更广泛的神经科学领域感兴趣。在这项研究计划的过程中，至少有六名高素质人员(HQP)将接受适用于神经科学和其他学科的最新技术的广泛培训。HQP将发展他们在批判性思维、口头陈述、科学写作、团队建设和网络方面的技能。这种培训环境将为他们在学术界、行业或政府的不同职业做好准备。**

Microglia are the immune cells of brain, which they protect from pathogens. In addition, microglial phagocytosis activity, cytokine production, and trophic factor secretion regulate neuronal plasticity, the key phenomenon that allows brain to reorganize its neural connections in response to new situations. While modulated microglial activity is beneficial, dysregulated microglial actions can cause neuronal dysfunction and promote cognitive deficits and neuronal death. These opposite roles of microglia are feasible because of their diverse functions attributed to specific activation phenotypes. ******The long term objective of my research is to reveal the molecular mechanisms of microglial actions in pathogen elimination, bystander neuronal injury, synapse maintenance and neuronal plasticity. This insight will allow us to explore the role of microglia on higher brain function including learning, memory and cognition. To address my long-term goals, I propose to explore the following short term (5 years) objectives utilizing poly(ADP-ribose) polymerase-1 (PARP-1) as a proven tool to reveal additional aspects of microglial signaling events. ***1) Determine the role of PARP-1 in regulation of microglial activation phenotype switch.***2) Identify transcription factors related to microglial activation phenotype changes. ***3) Dissect the molecular basis of microglial phagocytosis types. ******The proposed studies will be performed in vitro and some key points will be confirmed in in vivo. We will use microglia targeting molecular tools that I recently created to manipulate expression and activity of PARP-1, which has been suggested to serve as a key regulator of microglial functions. Microglial PARP-1 activation promotes pro-inflammatory responses and uncontrolled neuronal phagocytosis. Microglial PARP-1 inhibition dampens immune responses, while still allowing pathogen elimination. ******Outcomes from this proposed program will provide detailed mechanistic information about regulation of microglial functions that span from pathogen elimination to neuronal synaptic remodeling. Such information will be readily incorporated into the fields of neuroimmunology and synaptic plasticity, but be of interest also for the broader field of neuroscience. During the course of this research program at least six highly qualified personnel (HQP) will obtain training in a broad spectrum of up to date technologies applicable to neuroscience and other disciplines. HQP will develop their skills in critical thinking, oral presentations, scientific writing, team building and networking. This training environment will prepare them for diverse careers in academia, industry or government. **