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

描述(由申请人提供)：此NRSA F30奖项的目标是为我在塔夫茨大学医学院接受的医学博士/博士培训提供支持。一个全面的培训计划，包括课程作业和与拟议研究相关的活动，旨在促进作为临床医生研究员的成功职业追求。Y拟议的研究探讨了严重损伤后嗅觉上皮(OE)中静止的神经源性干细胞群(Hbcs)被激活的机制。我们最近发现，P53抑癌基因家族中的一员p63的减少是激活HBCs的必要条件和充分条件；然而，p63基因下调的潜在机制和后续机制仍不清楚。了解控制P63的机制，从而在HBCs中激活，对于开发靶向疗法来激活和扩大人类静止的神经干细胞群体至关重要。Notch信号以组织特异性的方式参与了对p63的调控。然而，Notch和P63之间的串扰在OE中仍然不清楚。我的工作重点是确定相邻细胞在细胞-细胞Notch信号中扮演的特定角色，以及Notch信号控制p63基因表达的分子机制。我的中心假设是，来自邻近支持细胞的Notch信号提供了关键的细胞间通信，从而显著有助于维持p63的表达。这是基于我的初步数据，这些数据表明Notch的过度表达增加了p63的表达，并表明去除支持细胞对于HBc的激活是必要的。我计划通过追求以下具体目标来检验这一假说：(1)系统地确定OE中每种细胞类型的损伤是如何导致HbCs激活的，以及(2)确定Notch信号调节HbCs中p63转录的分子机制。通过这项研究，我将获得关于调控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的神经干细胞群体的激活。因此，这项工作将有助于加深对神经干细胞生物学的基础科学理解，并提供一种激活休眠干细胞群体以进行神经组织修复的翻译方法。拟议的研究活动将与发展沟通、写作和指导技能的机会相结合，包括出席和在科学会议上发言，撰写手稿和助学金，以及在实验室监督本科生和研究生实习生。完成这些培训活动将为我实现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.