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

描述（由申请人提供）：NRSA F30奖学金的目的是为我的医学博士/博士学位提供支持。在塔夫茨大学医学院接受培训。一个全面的培训计划，包括课程作业和与拟议的研究相关的活动，旨在促进追求一个成功的职业生涯作为一个临床研究者。我们提出的研究探讨了嗅觉上皮（OE）中静止的神经源性干细胞群水平基底细胞（HBCs）在严重损伤后被激活的机制。我们最近发现，p53肿瘤抑制家族成员p63的减少是激活HBCs的必要和充分条件；然而，p63基因下调的潜在机制和后续机制尚不清楚。了解控制hbc中p63的激活机制对于开发靶向治疗方法来激活和扩大人类静止神经干细胞群至关重要。Notch信号以组织特异性的方式参与了p63的调控。然而，在OE中Notch和p63之间的串扰仍然不清楚。我的工作重点是确定邻近细胞在细胞间Notch信号传导到HBCs中的具体作用，以及Notch信号传导控制p63基因表达的分子机制。我的主要假设是来自邻近支持细胞的Notch信号提供了关键的细胞间通讯，这对维持p63的表达有重要作用。这是基于我的初步数据，这些数据表明Notch过表达会增加p63的表达，并表明去除支持细胞对于HBC激活是必要的。我计划通过以下具体目标来验证这一假设：(1)系统地确定OE中每种细胞类型的损伤是如何导致hbc信号激活的；(2)确定Notch信号调节hbc中p63转录的分子机制。通过这项研究，我将获得关于控制p63调控和HBC静止的信号事件的新知识，这将有助于更好地理解静止神经干细胞群体的激活。因此，这项工作将有助于进一步了解神经干细胞生物学的基础科学，也为激活休眠干细胞群体进行神经组织修复提供了一种转化方法。拟议的研究活动将与发展交流、写作和指导技能的机会相结合，包括参加科学会议并发表演讲，撰写手稿和赠款，以及指导实验室的本科生和研究生学员。这些培训活动的完成将为我成为一名独立资助的内科科学家的职业目标提供必要的基础。

DESCRIPTION (provided by applicant): 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.