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.
The goals of this project are to understand the molecular signaling mechanisms that regulate astrocyte function in health and pathology. We focus on a specific subpopulation of astrocytes that respond to the molecular signaling pathway Sonic hedgehog, and interrogate their role in the injured mammalian forebrain. Understanding the molecular mechanisms that drive astrocyte function in health and disease is critical to developing novel therapeutic strategies to treat the injured or diseased CNS.
|Garcia, A Denise R; Han, Young-Goo; Triplett, Jason W et al. (2018) The Elegance of Sonic Hedgehog: Emerging Novel Functions for a Classic Morphogen. J Neurosci 38:9338-9345|