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The regulation of p63 expression and activation to multipotency in HBCs of the ol

Daniel Herrick

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National Institutes of Health (NIH)
The goal of this NRSA F30 award is to provide support for my M.D. /Ph.D. training at Tufts University School of Medicine. A comprehensive training plan that encompasses both coursework and the activities associated with the proposed research is designed to facilitate the pursuit of a successful career as a clinician investigator. y proposed research investigates the mechanisms by which a quiescent neurogenic stem cell population in the olfactory epithelium (OE), horizontal basal cells (HBCs), is activated after severe injury. We have recently found that a decrease in p63, a member of the p53 tumor suppressor family, is necessary and sufficient for activation of HBCs; however, the mechanisms underlying and subsequent to p63 gene down regulation remain unknown. Understanding the mechanisms that govern p63, and thus activation, in HBCs is critical for developing targeted therapeutics for activating and expanding quiescent neural stem cell populations in humans. Notch signaling has been implicated in the regulation of p63 in a tissue-specific manner. However, the crosstalk between Notch and p63 in the OE remains unclear. My work focuses on identifying the specific roles neighboring cells play in cell-cell Notch signaling to HBCs and the molecular mechanism by which Notch signaling controls p63 gene expression. My central hypothesis is that Notch signaling from neighboring Sustentacular support cells provide critical cell-cell communication that significantly contributes to maintenance of p63 expression. This is based on my preliminary data that demonstrate that Notch overexpression increases p63 expression and suggests removal of Sustentacular support cells is necessary for HBC activation. I plan to test this hypothesis by pursuing the following Specific Aims: (1) Systematically determine how injury to each cell type in the OE is responsible for signaling HBCs to activate, and (2) determine the molecular mechanism by which Notch signaling regulates p63 transcription in HBCs. By performing this study, I will gain new knowledge on the signaling events that govern p63 regulation and HBC quiescence, which will help provide a better understanding of activation of quiescent neural stem cell populations. Thus, this work will help further the basic science understanding of neural stem cell biology and also provide a translational approach to activating dormant stem cell populations for neurologic tissue repair. The proposed research activity will be coupled with opportunities to develop communication, writing, and mentoring skills, including attending and presenting at scientific conferences, writin manuscripts and grants, and supervising undergraduate students and graduate trainees in the laboratory. Completion of these training activities will provide me with a necessary foundation to achieve my career goal of becoming an independently funded physician scientist.

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