Browsing Theses and Dissertations by Author "O'Brien, Jenny Alyssa"
The Role of Astrocyte-Derived Sonic Hedgehog in Stimulation of Neural Stem Cell Proliferation Following Traumatic Brain InjuryYang, Zeng-jie; Soprano, Dianne R.; Connolly, Denise; Ramirez, Servio H.; Black, Mark M. (Temple University. Libraries, 2019)Traumatic brain injury (TBI) is a major cause of disability worldwide. No effective treatment is currently available to restore function to the injured brain. After injury, massive neuronal death occurs which can result in long-lasting cognitive dysfunction. Following immediate mechanical damage, a series of secondary effects of injury occur including evolving neuronal damage, inflammation, astrocyte reactivation, blood brain barrier disruption and other physiological effects. Additionally, neural stem cell (NSC) proliferation has been observed following TBI, suggestive of an endogenous attempt to repair the brain. Stimulating proliferation of NSCs is a promising strategy to facilitate recovery following TBI, but the mechanisms underlying NSC proliferation remain unknown. In this work, we have addressed the following specific aims. In the first aim, we determined the role of Shh signaling in NSC proliferation after TBI. Using a fluid percussion model of TBI and conditional transgenic animal models, we investigated the role astrocytes play in NSC proliferation. Using a Sonic hedgehog (Shh) pathway inhibitor, we found that NSC proliferation after TBI relies on Shh signaling. In the second aim, we determined the role of astrocyte activation in NSC proliferation after TBI. Using transgenic tools, we determined that astrocytes are a major cellular source of Shh and that astrocyte-specific deletion of Shh inhibited NSC proliferation. This indicates that NSC proliferation relies on Shh signaling and that astrocytes represent the key cellular source. In the final aim, we sought to define the functional requirement of Nestin in NSC proliferation. Recent studies in our lab found that Nestin, an intermediate filament protein predominantly expressed by NSCs, played a role in Shh signaling in the setting of medulloblastoma cells. Here, we found that knockdown of Nestin impaired Shh signal transduction and Shh-driven proliferation in NSCs. Further, we generated a new mouse model allowing conditional deletion of Nestin in NSCs to determine whether Nestin played a similar role a non-neoplastic setting. Conditional deletion of Nestin in NSCs abolished the proliferation of hippocampal NSCs after TBI. These findings reveal the critical role of Nestin in Shh signaling and proliferation in NSCs following TBI. Our studies elucidate the cellular and molecular basis for NSC proliferation after TBI, which pave the road for development of therapeutic approaches to treat TBI by augmenting endogenous NSC regeneration.