Molecular Regulation of Microglia Behavior

描述（由申请人提供）：神经元损伤和变性伴随着先天免疫系统的炎症反应。中枢神经系统组织具有高度特化的先天免疫反应，主要由常驻巨噬细胞群体小胶质细胞介导。小胶质细胞在胚胎发育早期侵入中枢神经系统，是一种高度特化的髓系细胞，具有独特的特征和功能。小胶质细胞行为的一个独特方面是通常是静止的，表达与其他特化巨噬细胞行为相关的标记物很少。然而，就像巨噬细胞一样，小胶质细胞可以通过采取各种行为来应对中枢神经系统环境的变化。当小胶质细胞对环境变化做出反应时，它们可以执行与“经典”巨噬细胞激活相关的功能，这种功能进化为对细菌和病毒病原体的有效反应，以及参与平息炎症反应或参与组织修复过程。目前，关于小胶质细胞在急性或慢性损伤中哪种功能占主导地位存在争议，也没有明确的方法通过实验诱导小胶质细胞采取一套特定的行为。我们已经确定p53是一种转录调节因子，可促进与小胶质细胞经典激活相关的行为，而p53缺乏会产生与小胶质细胞抗炎和组织修复功能相关的基因表达模式。p53影响小胶质细胞行为的一种机制被确定为第二种转录因子c-Maf的负调控。c-Maf转录因子是已知的淋巴细胞和髓细胞分化的调节因子，通常被观察到促进先天和适应性免疫系统的抗炎/组织修复手臂。本研究将进一步探索这些发现，首先证明巨噬细胞中c-Maf的功能在小胶质细胞中重现，其次确定p53影响c-Maf表达的分子机制，第三确定p53是否在体内调节小胶质细胞的行为，使用Cre/lox系统以特定的时间和细胞类型灭活p53。

DESCRIPTION (provided by applicant): Neuronal injury and degeneration are accompanied by inflammatory responses from the innate immune system. Central nervous system tissues have highly specialized innate immune responses mediated primarily by microglia, the resident macrophage population. Microglia invade the CNS early in embryonic development and are a highly specialized cell of myeloid origin with unique features and functions. One of those unique aspects of microglia behavior is that are normally quiescent, expressing few markers associated with other specialized macrophage behaviors. Like their macrophage cousins however, microglia can respond to changes in the CNS environment by adopting a variety of behaviors. When microglia respond to changes in their environment, they can perform functions associated with "classical" macrophage activation that evolved as effective responses to bacterial and viral pathogens as well as those involved in quelling an inflammatory response or participating in the process of tissue repair. Currently, there is debate regarding which microglia functions dominate during acute or chronic injuries and no clear method of experimentally inducing microglia to adopt a specific set of behaviors. We have identified p53 as a transcriptional regulator that promotes behaviors associated with classical activation in microglia while p53 deficiency yields gene expression patterns associated with anti-inflammatory and tissue repair functions in microglia. One mechanism by which p53 influences microglia behavior was identified as negative regulation of a second transcription factor, c-Maf. The c-Maf transcription factor is a known regulator of both lymphocyte and myeloid cell differentiation, generally observed to promote the anti-inflammatory/tissue repair arm of both the innate and adaptive immune system. This proposal will further explore these discoveries by first demonstrating that the function of c-Maf in macrophages is recapitulated in microglia, second identifying the molecular mechanisms by which p53 influences c-Maf expression and third determining if p53 modulates microglia behaviors in vivo using the Cre/lox system to inactivate p53 in a time and cell type specific fashion. PUBLIC HEALTH RELEVANCE: A wide variety of nervous system disease and injury states are associated with a robust inflammatory response. Currently there is no clear understanding of the molecules that regulate whether the cells responsible for this inflammatory response will behave in a manner that helps protect nervous system tissue or exacerbates the injury process. This proposal aims to study a molecular pathway that regulates inflammatory behavior outside of the nervous system to determine if it could be harnessed as a method of maximizing recovery or preventing further degeneration in a variety of diseases including stroke, Alzheimer's disease and vascular dementia.