Candidate: My overarching goal is to understand the molecular mechanism that regulate self-renewal and differentiation of neural stem cell during homeostasis, regeneration and in neoplasms. To achieve this goal, I am pursuing a career in stem cell biology, focusing on the brain. My graduate work focused on characterizing molecularly distinct stem cell populations in patient-derived brain tumors and understanding their roles in tumorigenesis. In order to gain in depth experience on studying how stem cell behaviors are regulated in vivo, I chose to join Dr. Alexandra Joyner?s laboratory to study developmental neurobiology and regeneration. Here, I study the function of stem cells during repair of the developing and adult cerebellum. The main purpose of this grant is to provide the skills and knowledge that I need to build my own independent research program. Environment: Dr. Joyner?s lab provides a stimulating environment for me to gain research and mentoring skills to launch my career as an independent investigator. Under her mentorship and with the help of my colleagues along with the supportive institutional environment, I will learn the most sophisticated mouse models and developmental biology techniques that are crucial to study stem cells in vivo. In addition to Dr. Joyner, my advisors and collaborators will provide necessary training in genomics/epigenomics approaches to supplement my required knowledge and training in order to establish a multidisciplinary research program. Research: Regeneration in the brain is limited. I submit that an understanding of the gene regulatory networks that regulate the plasticity of neural stem/progenitor populations and their ability to self-renew and differentiate is crucial for discovering how to stimulate the regenerative potential of the brain. Our lab recently discovered that the neonatal cerebellum has a surprisingly high regenerative potential as it can recover from ablation of at least two types of neurons, making it an excellent system to uncover molecular events required for successful regeneration. Upon depletion of granule cell precursors, a subpopulation of Nestin-expressing progenitors (NEPs) change their fate from glia to produce excitatory granule neurons in a Hedgehog (HH)-dependent manner. Furthermore, I found that rare NEP-like cells exist in the adult cerebellum, and HH signaling and injury synergize to expand the population. However, their regenerative yield is limited.
The aim of this proposal is to identify the signaling pathways and gene regulatory networks that control the regenerative response of NEPs to injury in the newborn cerebellum and determine how it differs in the adult. I will combine mouse genetics and injury models with whole genome transcriptomic/epigenomic analyses to dissect and compare the gene expression profiles of individual NEPs in the normal and injured newborn and adult cerebellum. In vitro and in vivo stem cells assays will then identify signaling pathways that stimulate self-renewal and reprogramming during regeneration, and candidate pro-regenerative pathways will be tested for their ability to enhance repair. My findings will provide a basis for in vivo manipulation of stem cells to facilitate repair of the brain.
The cerebellum, which is the region of the brain that is important for motor coordination, can regenerate after injury during development. Neural stem cells present in the neonatal cerebellum replenish the lost cells after injury, however their number and regenerative capacity decreases with age. This study aims to understand how the stem cells achieve repair during development, why their regenerative potential decreases with age, and how the knowledge gained from studying the developing cerebellum can be used to formulate strategies to enable and enhance regeneration.
