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

多能性 HBC 中 p63 表达和激活的调节

基本信息

批准号：
8718356
负责人：
Daniel Herrick
金额：
$ 3.83万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-12 至 2019-03-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8718356
关键词：
Ablation Address Adult Animals Anosmia Apical Autologous Award Basal Cell Basal lamina Basic Science Breeding Cell Communication Cell physiology Cells Communication Consensus Coupled Cues Cytokeratin Data Diphtheria Toxin Doctor of Medicine Doctor of Philosophy Down-Regulation Duct (organ) structure Elderly Environment Epithelial Epithelial Cells Event Excision Family Foundations Funding Gene Expression Gene Expression Profiling Gene Expression Regulation Genetic Recombination Genetic Transcription Gland Goals Grant Human Injury Joints Knock-out Knowledge Laboratories Lead Life Ligands Maintenance Manuscripts Mediating Mentors Messenger RNA Molecular Mus National Research Service Awards Natural regeneration Nature Nervous system structure Neuroglia Neurologic Neurons Notch Signaling Pathway Olfactory Epithelium Pathway interactions Physicians Play Population Protein p53 Proteins Publishing Recruitment Activity Regimen Regulation Research Research Activity Research Personnel Reserve Stem Cell Role Scientist Signal Transduction Site Source Stem cell transplant Stem cells Stimulus Study models Supporting Cell Tamoxifen Testing Tetanus Helper Peptide Tetracyclines Tissues Training Training Activity Transcription Coactivator Transgenes Universities Work Writing adult neurogenesis age related aged base career cell type central nervous system injury design exhaustion gene repression in vitro Assay in vivo injured intercellular communication medical schools member methyl bromide monolayer nerve stem cell notch protein olfactory bulb overexpression pluripotency promoter public health relevance relating to nervous system repaired response self-renewal skills small hairpin RNA stem stem cell biology stem cell population sustentacular cell symposium therapeutic target tissue repair transcription factor translational approach undergraduate student

项目摘要

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.

描述（由申请人提供）：该 NRSA F30 奖项的目标是为我的医学博士/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研究相关的活动，旨在促进临床医生研究者追求成功的职业生涯。我们提出的研究调查了嗅上皮（OE）中静止的神经源性干细胞群、水平基底细胞（HBC）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 的减少对于 HBC 的激活是必要且充分的；然而，p63 基因下调的潜在机制和后续机制仍不清楚。了解 HBC 中 p63 的控制机制以及激活机制对于开发激活和扩大人类静止神经干细胞群的靶向疗法至关重要。 Notch 信号传导以组织特异性方式参与 p63 的调节。然而，Notch 和 OE 中 p63 之间的串扰仍不清楚。我的工作重点是确定邻近细胞在 HBC 的细胞 Notch 信号传导中所起的具体作用，以及 Notch 信号传导控制 p63 基因表达的分子机制。我的中心假设是，来自邻近支持细胞的 Notch 信号传导提供了关键的细胞间通讯，对维持 p63 表达有显着贡献。这是基于我的初步数据，该数据证明 Notch 过度表达会增加 p63 表达，并表明去除支撑支持细胞对于 HBC 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设：(1) 系统地确定 OE 中每种细胞类型的损伤如何导致 HBC 信号激活，以及 (2) 确定 Notch 信号传导调节 p63 转录的分子机制在 HBC 中。通过这项研究，我将获得有关控制 p63 调节和 HBC 静止的信号事件的新知识，这将有助于更好地了解静止神经干细胞群的激活。因此，这项工作将有助于进一步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以修复神经组织的转化方法。拟议的研究活动将伴随着发展沟通、写作和指导技能的机会，包括参加和在科学会议上发言、撰写手稿和资助，以及在实验室监督本科生和研究生学员。完成这些培训活动将为我实现成为一名独立资助的医师科学家的职业目标提供必要的基础。