Despite recent advances in biomedical sciences, treatment options remain limited for patients suffering from stroke or other forms of brain injuries. Endogenous regenerative capacities in the brain hold great therapeutic promise for nervous system repair after disease and injury. While in recent years much research effort has focused on production and integration of neurons, new astrocytes are also made following brain injury, and their functional importance during repair is just beginning to be understood. In contrast to the well- investigated area of adult neurogenesis, relatively little is known about the cellular and molecular mechanisms controlling new astrocyte production in the adult brain in health and disease. Using a combination of mouse genetics, molecular biology, and multiphoton live-imaging, we plan to elucidate the steps necessary to produce new astrocytes and glial scars after brain injury, as well as to understand their functional roles in post-stroke responses and tissue homeostasis. Our preliminary results show that extracellular matrix protein Thrombospondin 4 (Thbs4) is critically important for glial scar formation to stop continued bleeding, as well as motor-behavioral functional recovery after injury. Furthermore, Thbs4 and NFIA transcription factor form a signaling axis to promote injury-induced astrogenesis. We plan to further explore these unexpected observations by determining the following: 1) whether cortical glial scar formation after injury is specifically controlled by newly born astrocytes from the SVZ niche migrating to cortical injury, and/or mediated by Thbs4 protein itself, delivered by newly generated astrocytes to act on parenchymal astrocytes/progenitors at the injury site; 2) what are the transcriptional pathways controlled by NFIA to regulate injury-induced astrogenesis, the key step required to initiate glial scar formation; and 3) whether Thbs4-expressing astrocyte subset constitutes a progenitor population, that can be acted-on by Thbs4 and NFIA proteins to produce new astrocytes after injury. Tackling the basic cellular and molecular mechanisms controlling injury-induced astrogenesis, and the roles that these new astrocytes play in tissue homeostasis, should further our understanding of astrocyte biology in health and disease.
Modern medicine has few treatment options for patients suffering from central nervous system (CNS) injuries such as stroke and trauma. Our proposal examines a new hypothesis that in response to brain injury, two important proteins act in synergy to induce resident progenitor cells to produce new astrocytes, which then are critical for proper glial scar formation to stop bleeding and facilitate repair. Results from these studies should provide needed substrates for future strategies aimed at treating stroke and other CNS injuries.
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