The Role of p53 in the Regulation of Neuroinflammation

描述(由申请人提供)：在受伤、中风和几种神经退行性疾病期间，神经系统会发生炎症。中枢神经系统(CNS)的一些退行性疾病，如多发性硬化症，主要是由异常炎症引起的。炎症如何影响神经变性尚不完全清楚，但可能涉及被称为小胶质细胞的常驻炎症细胞的重要作用。暴露于感染剂、受损的中枢神经系统组织或异常蛋白质堆积(如阿尔茨海默病中积聚的β-淀粉样蛋白)的小胶质细胞会释放炎症介质，这些介质通常对中枢神经系统细胞有害，并可能产生慢性炎症的恶性循环。长期暴露在炎症状态下会导致活性氧物种(ROS)的积累，这可能会损害包括DNA在内的各种细胞成分。这可能会导致细胞系统的激活，从而诱导一种称为细胞凋亡的细胞自杀程序。在使用体外炎症诱导的神经元损伤模型的实验中，我们观察到神经元和小胶质细胞都需要P53作为重要的细胞凋亡调节因子，才能产生炎性神经毒性。为了确定p53如何参与小胶质细胞对促炎刺激的反应，我们检测了从野生型和p53缺陷小鼠获得的培养小胶质细胞的整体基因表达谱。这两种基因类型小胶质细胞基因表达的差异，再加上P53缺陷小胶质细胞释放细胞因子的额外数据，导致了P53参与决定小胶质细胞对炎症信号的激活表型的假设。小胶质细胞是巨噬细胞系中的细胞，已有几种类型的巨噬细胞激活的特征。巨噬细胞激活的两种类型包括“经典的”组织破坏性激活和当巨噬细胞参与组织修复时炎症反应下调调节阶段的“替代”激活。在这方面，我们将解决的问题是，p53是在髓系分化过程中作用于影响极化小胶质细胞激活的可能性，还是与小胶质细胞对特定激活信号的反应同时发生。我们还将研究p53如何与c-Maf相互作用，c-Maf是小胶质细胞中由p53抑制的转录因子，它在确定巨噬细胞激活模式方面具有先前描述的作用。最后，我们将确定P53是否在炎性刺激下转变为小胶质细胞线粒体，从而影响线粒体的完整性和ROS的产生。 与公共卫生相关：炎症是许多常见神经系统疾病的关键病理成分，包括阿尔茨海默病、帕金森氏病和中风。小胶质细胞是驻留在神经系统中的炎性细胞，我们目前还不完全了解这些细胞如何对损伤或疾病做出反应。拟议的实验将增强我们对P53的理解，P53是细胞分裂和生存的关键调节因子，也可能是小胶质细胞如何对启动或持续炎症的刺激做出反应的根本决定因素。

DESCRIPTION (provided by applicant): Inflammation in the nervous system occurs during injury, stroke and several neurodegenerative diseases. Some degenerative diseases of the central nervous system (CNS) such as multiple sclerosis occur primarily due to abnormal inflammation. How inflammation impacts neurodegeneration is not completely understood but likely involves important roles for resident inflammatory cells known as microglia. Microglia exposed to infectious agents, injured CNS tissue, or abnormal protein accumulations (such as the beta-amyloid protein that accumulates in Alzheimer's disease), release inflammatory mediators that are often toxic to CNS cells and may produce a vicious cycle of chronic inflammation. Long term exposure to an inflammatory state can lead to the accumulation of reactive oxygen species (ROS) which may damage a variety of cellular components including DNA. This can lead to activation of cellular systems evolved to induce a cell suicide program called apoptosis. During experiments using an in vitro model of inflammation induced neuronal injury we observed that an important regulator of apoptosis, p53 is required in both neurons and microglia for inflammatory neurotoxicity. To determine how p53 is involved in the microglia response to a pro-inflammatory stimulus we examined global gene expression profiles from cultured microglia obtained from wild type and p53 deficient mice. The difference in gene expression between these two genotypes of microglia in conjunction with additional data on cytokine release from p53 deficient microglia led to the hypothesis that p53 participates in determining the activation phenotype in microglia cells in response to inflammatory signals. Microglia are cells in the macrophage linage, and several types of macrophage activation have been characterized. Two types of macrophage activation include "classical" tissue destructive activation and "alternative" activation in the down regulatory phase of the inflammatory response when macrophages participate in tissue repair. In this we will address the question of whether p53 acts during myeloid differentiation to influence to potential for polarized microglia activation or concurrently with the microglia response to a specific activation signal. We will also examine how p53 may interact with c-Maf, a transcription factor repressed by p53 in microglia, which has a previously described role in determining macrophage activation patterns. Finally, we will determine if p53 transits to microglia mitochondria in response to inflammatory stimuli, thereby impacting mitochondrial integrity and ROS generation. PUBLIC HEALTH RELEVANCE: Inflammation is a key pathological component of many common disease of the nervous system including Alzheimer's disease, Parkinson's disease and Stroke. Microglia are inflammatory cells that reside in the nervous system and we do not currently have a complete understanding of how these cells respond to injury or disease. The proposed experiments will enhance our understanding of how p53, a key regulator of cell division and survival may also be a fundamental determinate of how microglia respond to stimuli that initiate or perpetuate inflammation.