Molecular Mechanisms of Neural Stem Cell Quiescence in Aging and Cancer

Audesse, Amanda Jane

Full Metadata

Overview

Year:: 2022
Contributor:: Audesse, Amanda Jane (creator); Webb, Ashley (Advisor); Fallon, Justin (Reader); Barnea, Gilad (Reader); Paik, Jihye (Reader); Brown University. Department of Neuroscience (sponsor)
Genre:: theses
Subject:: Neural stem cells; stem cell aging
Extent:: xxi, 307 p.

Files

Description

Abstract:: Adult neurogenesis is the process by which new neurons form in the adult brain. This process supports cognitive functions in rodents, and likely in humans as well. Neurogenesis is reduced during aging, and this decline is associated with cognitive dysfunction. New neurons are generated from neural stem cells (NSCs), which mostly reside in a quiescent state in the brain. During aging, the ability of quiescent NSCs to become activated and form new neurons is reduced. A number of studies suggest that the depth of quiescence becomes enhanced throughout aging, resulting in a deeper state of dormancy. However, the precise molecular mechanisms that regulate quiescence remain inadequately understood across stem cell compartments, including in the adult brain. Quiescence programs are also thought to be hijacked in the context of cancer. Glioma stem cells (GSCs), which share many features of endogenous NSCs, are the source of glioblastoma (GBM). Quiescent GSCs are particularly dangerous because they evade therapeutic intervention and can reactivate to promote tumor progression. Here, we investigate the mechanisms that maintain quiescence in young, aged, and tumorigenic stem cells in the brain. Specifically, we identify the pro-longevity transcription factor, FOXO3, as a central regulator of genomic programs involved in protein and metabolic quality control in NSCs and GSCs. More broadly, we characterize metabolic profiles and organelle content in activated and quiescent NSCs, leading to new insights into the mechanisms supporting these distinct cellular states. Together, the work presented here expands our understanding of the transcriptional and metabolic mechanisms of quiescence in NSCs that may become perturbed throughout aging or tumorigenesis. We identify novel pathways that may act as therapeutic targets to ameliorate the enhanced quiescence of aged NSCs to rescue neurogenesis and improve cognitive function in the aged brain. Our work also lays the foundation for future efforts to identify markers of quiescent GSCs in bulk tumors and sensitize these cells to therapeutic intervention to improve patient outcomes.
Notes:: Thesis (Ph. D.)--Brown University, 2022

Content

Citation

Audesse, Amanda Jane, "Molecular Mechanisms of Neural Stem Cell Quiescence in Aging and Cancer" (2022). Neuroscience Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:7vsew59w/

Relations

Collection:

Neuroscience Theses and Dissertations

Theses and Dissertations for the Neuroscience department.
...