Molecular regulation of cell fate and progenitor function in the distal human respiratory airways

项目概要/摘要 该建议描述了一个五年的培训计划，以发展独立的研究事业， 远端气道上皮在人肺损伤和再生中的作用。具体而言，申请人力求 为了了解一种新的人类特异性分泌群体呼吸道分泌的调节， 细胞（RASC），它可以作为肺泡2型（AT 2）细胞的祖细胞，并了解这个群体如何 在慢性阻塞性肺疾病（COPD）中发生改变。申请人是在她的最后一年肺和 宾夕法尼亚大学医院重症监护奖学金，曾接受过细胞生物学博士培训 和分子生物学，重点是细胞命运调控。该奖项的目标是完善和发展技能 这将是必要的一个成功的职业生涯作为一个独立的调查，包括专业知识在表观基因组学， 哺乳动物基因编辑和先进的生物信息学分析。这个奖项的导师是爱德华博士 Morrisey是国际知名的肺再生和修复专家， 培训记录。此外，一个由互补和多样化科学家组成的咨询委员会已 为培训计划提供广度和深度。申请人将受益于无与伦比的 指导，资源和科学界在宾夕法尼亚大学和毫无保留的支持， 她的机构。 这项提案的目的是扩大我们对人类一个未充分研究的区域的了解。 肺，呼吸细支气管。小鼠中没有呼吸性细支气管，因此它们在肺损伤中起作用， 再生和修复基本上是未知的，往往被忽视。最近的数据表明， 细支气管是COPD的损伤部位，强调需要了解分子调节和 在这个生态位内的细胞群的功能。这个项目将研究最近一种新的细胞类型的调节 在人类呼吸性细支气管RASC中发现。RASC可以作为AT 2细胞的祖细胞，并且是 在COPD中转录改变，这表明它们的功能可能会改变，并有助于 这一高度流行的疾病的发病机制。这突出了研究这种细胞类型的科学需要， 它对伤害的反应。成功完成这些拟议的研究将解决中心假设， RASC的细胞命运和祖细胞功能通过Notch信号传导和 转录因子S 0X 4，并且这种祖细胞功能在COPD中改变。这将通过以下方式实现： 多种技术，包括人类胚胎干细胞建模，下一代测序， 原代人肺组织的表观遗传学分析。这些研究将为新型肺提供重要的见解 因此，本发明的肺再生系统是肺祖细胞的一部分，并且在COPD和更广泛的肺再生中具有治疗影响的高潜力。

PROJECT SUMMARY/ABSTRACT This proposal describes a five-year training plan for the development of an independent research career focused on the role of the distal airway epithelium in human lung injury and regeneration. Specifically, the applicant strives to understand the regulation of a novel human specific secretory population called respiratory airway secretory cells (RASCs), which can act as progenitors for alveolar type 2 (AT2) cells, and understand how this population is altered in Chronic Obstructive Pulmonary Disease (COPD). The applicant is in her final year of Pulmonary and Critical Care fellowship at the Hospital of the University of Pennsylvania with previous PhD training in cellular and molecular biology with a focus on cell fate regulation. The goals of this award are to refine and develop skills that will be necessary for a successful career as an independent investigator including expertise in epigenomics, mammalian gene editing, and advanced bioinformatic analysis. The mentor for this award is Dr. Edward Morrisey, an internationally renowned expert in lung regeneration and repair with an outstanding and expansive training record. Furthermore, an advisory committee of complementary and diverse scientists has been assembled to provide breadth and depth to the training plan. The applicant will benefit from the unparalleled mentoring, resources and scientific community at the University of Pennsylvania and the unreserved support of her institution. The aims of this proposal are focused on expanding our knowledge of an understudied region of the human lung, the respiratory bronchioles. Respiratory bronchioles are absent in mouse and hence their role in lung injury, regeneration and repair is essentially unknown and often over-looked. Recent data demonstrate that respiratory bronchioles are a site of injury in COPD, highlighting the need to understand the molecular regulation and function of cell populations within this niche. This project will examine the regulation of a novel cell type recently identified in the human respiratory bronchioles, RASCs. RASCs can serve as progenitors for AT2 cells, and are transcriptionally altered in COPD, suggesting that their function could be altered in, and contribute to, the pathogenesis of this highly prevalent disease. This highlights the scientific need to investigate this cell type and its response to injury. Successful completion of these proposed studies will address the central hypothesis that the cell fate and progenitor function of RASCs is regulated through a combination of Notch signaling and the transcription factor SOX4, and that this progenitor function is altered in COPD. This will be accomplished through multiple techniques including human embryonic stem cell modeling, next-generation sequencing, and advanced epigenetic analysis of primary human lung tissue. These studies will provide significant insight into a novel lung progenitor cell and have a high potential for therapeutic impact in COPD and lung regeneration more broadly.