Investigator: Ashley Webb, Brown University

Mentor: Justin Fallon, Brown University

Scientific Theme: Neuroscience

Abstract: Adult neural stem cells (NSCs) have the capacity to form new neurons in the adult mammalian brain, and are a promising source for regenerative therapies in the long term. The adult brain contains two distinct populations of stem cells: active NSCs and quiescent NSCs. The quiescent NSCs are thought to be the source of actively proliferating NSCs, and provide a long term reserve population of cells with regenerative potential. While the quiescent cells rarely divide, they are actively maintained in this state, and have the potential to be reactivated and form new neurons. However, the mechanisms governing quiescent NSC function and activation are unknown. There is a currently a critical need to understand these mechanisms in order to utilize NSCs to their full therapeutic potential. The overarching goal of this research program is to uncover the mechanisms underlying NSC quiescence in the adult brain, and discover strategies to improve the neurogenic capacity of NSCs in the brain during aging. This proposal with focus of the transcription factor networks that promote a state of NSC quiescence, which is distinct from the state of active NSC proliferation. Specifically, the Aims proposed in this grant will determine how quiescent NSCs are directly regulated at the transcriptional level. The central hypothesis of this proposal is that transcription factor FOXO3, which is a central regulator of both aging and stem cells, functions in a transcriptional network to directly regulate a program of quiescence related genes that are critical for NSC function. The goal of Specific Aim 1 is to identify the key transcription factors, such as FOXO3, that directly promote adult NSC quiescence, and determine their downstream functional transcriptional networks. The experiments proposed in Specific Aim 2 will identify the transcription factor interactions that maintain the balance between NSC quiescence and neurogenesis in adult NSCs. Together, these aims will significantly advance our understanding of how gene networks are coordinated to maintain quiescent NSCs, which are a source of new neurons. In the longer term, an understanding of these mechanisms will reveal strategies to manipulate specific genes and pathways in NSCs in vivo or in vitro in order to promote neurogenesis during aging or in disease states.

Human Health Relevance: This study will identify the processes that regulate neural stem cell function and help us understand why the formation of new neurons declines with age. Ultimately, this work will contribute to the development of new therapies to prevent the age-dependent decline in new neuron formation and preserve learning and memory functions during aging and disease states such as stroke, spinal cord injury and Alzheimer’s disease.