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

• 批准号: 9235271
• 负责人: Daniel Herrick
• 金额: $ 4.9万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 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/9235271
• 关键词: Ablation; Acute; Address; Adult; Animals; Anosmia; Apical; Autologous; Award; Basal Cell; Basal lamina; Basic Science; Cell Communication; Cell physiology; Cells; Cellular biology; 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; Immobilization; Injury; Joints; Knock-out; Knowledge; Laboratories; Lead; Life; Ligands; LoxP-flanked allele; 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; Supervision; Supporting Cell; TP53 gene; 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; horizontal cell; 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 cell biology; stem cell population; sustentacular cell; symposium; targeted treatment; tissue repair; transcription factor; translational approach; undergraduate student

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）：这个NRSA F30奖的目标是为我的医学博士提供支持。/博士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临床研究者。y提出的研究调查了嗅觉上皮（OE）中的静止神经源性干细胞群，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肿瘤抑制基因家族成员p63的减少是HBCs激活的必要和充分条件;然而，p63基因下调的机制仍然未知。了解HBC中控制p63并因此激活的机制对于开发用于激活和扩增人类静止神经干细胞群的靶向治疗剂至关重要。Notch信号传导以组织特异性方式参与p63的调节。然而，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特定的作用，邻近细胞在细胞间Notch信号传导到HBCs和Notch信号控制p63基因表达的分子机制。我的中心假设是，来自相邻支持细胞的Notch信号提供了重要的细胞间通讯，这对维持p63表达有重要作用。这是基于我的初步数据，这些数据表明Notch过表达增加了p63表达，并表明去除支持细胞对于HBC激活是必要的。我计划通过追求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如何负责HBC激活的信号，以及（2）确定Notch信号调节HBC中p63转录的分子机制。通过进行这项研究，我将获得关于控制p63调节和HBC静止的信号事件的新知识，这将有助于更好地理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了解神经干细胞生物学的基础科学，也提供了一个转化的方法来激活休眠的干细胞群体神经组织修复。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，包括参加和出席科学会议，撰写手稿和赠款，并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提供必要的基础，以实现我的职业目标，成为一名独立资助的医生科学家。