Molecular Regulation of Microglia Behavior

描述（由申请人提供）：神经元损伤和变性伴有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应答，主要由小胶质细胞介导，小胶质细胞是巨噬细胞的常驻群体。小胶质细胞在胚胎发育早期侵入CNS，并且是具有独特特征和功能的高度特化的髓样起源细胞。小胶质细胞行为的一个独特方面是通常是静止的，表达很少与其他专门的巨噬细胞行为相关的标志物。然而，像它们的巨噬细胞表亲一样，小胶质细胞可以通过采取各种行为来响应CNS环境的变化。当小胶质细胞对环境的变化做出反应时，它们可以执行与“经典”巨噬细胞激活相关的功能，这些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的功能。目前，关于小胶质细胞在急性或慢性损伤期间的功能占主导地位，并且没有明确的实验诱导小胶质细胞采取特定行为的方法存在争议。我们已经确定p53作为一种转录调节因子，促进与小胶质细胞中的经典激活相关的行为，而p53缺陷产生与小胶质细胞中的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个转录因子c-Maf的负调控。c-Maf转录因子是淋巴细胞和骨髓细胞分化的已知调节因子，通常观察到促进先天性和适应性免疫系统的抗炎/组织修复臂。该提案将进一步探索这些发现，首先证明，在巨噬细胞中的c-Maf的功能是重演的小胶质细胞，第二确定的分子机制，p53影响c-Maf的表达和第三确定是否p53调节小胶质细胞的行为在体内使用的Cre/lox系统，以阻止p53在时间和细胞类型特异性的方式。

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.