The role of Sonic hedgehog signaling on astrocyte function in the adult CNS

 描述(申请人提供)：这项研究的广泛目标是了解受损中枢神经系统中调节星形胶质细胞功能的分子机制。在哺乳动物中枢神经系统中，星形胶质细胞包括一组复杂的、具有不同功能特性的细胞。其中最突出的是它们作为神经系统对创伤反应的基本组成部分，扮演着神经炎症和神经保护的角色，服务于保卫中枢神经系统和恢复动态平衡。神经系统损伤或疾病后，星形胶质细胞经历一系列的形态、生化和生理变化，统称为反应性星形胶质细胞增多症。尽管历史上反应性星形胶质细胞是中枢神经系统再生和功能恢复的障碍，但它们的神经保护功能正在得到越来越多的认可，包括限制炎症和随后的继发性损害。事实上，星形胶质细胞正在成为开发新疗法的靶点，旨在治疗受伤或患病的中枢神经系统。然而，在我们对反应性星形胶质细胞如何实现如此多样化的功能的理解中，仍然存在关键的差距。最近，在健康的成人大脑中发现了一种星形胶质细胞亚群，它表达转录因子Gli1，表明高活性的Sonic hedgehog(Shh)信号。药理学研究表明Shh在受损的中枢神经系统中具有神经保护作用。然而，Shh促进神经保护的确切机制，以及这些机制是否由星形胶质细胞介导，仍然知之甚少。这项研究使用小鼠的分子遗传学来直接询问Shh信号在反应性星形胶质细胞和胶质细胞增生中的作用。Gli1星形胶质细胞将被标记和识别，随后将使用单侧前脑刺伤触发反应性胶质增生。反应性Gli1星形胶质细胞是否表现出与Gli1阴性星形胶质细胞不同的特殊细胞特性将被检测。为了探讨Shh活性在反应性胶质细胞增生症中的功能意义，将使用靶向分子消融方法来检查胶质细胞增生症是如何受损的。最后，生理性和反应性Gli1星形胶质细胞的转录图谱将被执行，以确定直接受Shh信号调控的基因表达程序。总之，这些研究将为Shh信号在反应性星形胶质细胞的多方面细胞活动中的作用提供新的见解。了解反应性星形胶质细胞的多种作用和功能特性的分子机制，对于理解如何促进其神经保护作用，同时减弱其神经炎症功能是重要的一步。

 DESCRIPTION (provided by applicant): The broad objective of this study is to understand molecular mechanisms regulating astrocyte function in the injured CNS. Astrocytes encompass a complex and heterogeneous population of cells in the mammalian CNS with diverse functional properties. Prominent among these are their roles as essential components of the nervous system response to trauma, playing both neuroinflammatory and neuroprotective roles that serve to defend the CNS and restore homeostasis. Following nervous system injury or disease, astrocytes undergo a broad array of morphological, biochemical, and physiological changes collectively referred to as reactive astrogliosis. Despite their historical characterization as impediments to CNS regeneration and functional recovery, reactive astrocytes are gaining increasing recognition for their neuroprotective functions that include limiting inflammation and subsequent secondary damage. Indeed, astrocytes are emerging as targets for developing novel therapies aimed at treating the injured or diseased CNS. However critical gaps remain in our understanding of how reactive astrocytes achieve such diversity of function. Recently, a subpopulation of astrocytes in the healthy, adult brain has been identified that expresses the transcription factor, Gli1, indicating high and active Sonic hedgehog (Shh) signaling. Pharmacological studies point to a neuroprotective role for Shh in the injured CNS. However, the precise mechanisms by which Shh promotes neuroprotection, and whether those mechanisms are mediated by astrocytes, remain poorly understood. This study uses mouse molecular genetics to perform direct interrogations of the role of Shh signaling in reactive astrocytes and gliosis. Gli1 astrocytes will be marked and identified, and reactive gliosis will subsequently be triggered using a unilateral forebrain stab injury. Whether reactive Gli1 astrocytes exhibit specific cellular properties distinct from Gli1-negative astrocytes will be examined. To interrogate the functional significance of Shh activity in reactive gliosis, a targete molecular ablation approach will be used to examine how gliosis is impaired. Finally, transcriptional profiling of physiological and reactive Gli1 astrocytes will be performed in order o identify gene expression programs that are directly regulated by Shh signaling. Collectively, these studies will provide novel insight into the role of Shh signaling in the multifaceted cellula activities of reactive astrocytes. Understanding the molecular mechanisms that distinguish the multiple roles and functional properties of reactive astrocytes is an important step towards understanding how to promote their neuroprotective roles, while attenuating their neuroinflammatory functions.