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

项目摘要/摘要 这项建议描述了一项为期五年的培训计划，旨在发展以独立研究为重点的职业生涯 论远端呼吸道上皮在人肺损伤和再生中的作用。具体地说，申请人努力 了解一种新的人类特有的分泌群--呼吸道分泌物的调节 细胞(RASCs)，它可以作为肺泡2型(AT2)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。申请者在她的肺和肺的最后一年 在宾夕法尼亚大学医院接受过细胞学博士培训的重症监护研究员 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。 这将是成功的独立研究人员职业生涯所必需的，包括表观基因组学方面的专业知识， 哺乳动物基因编辑和高级生物信息学分析。这一奖项的导师是爱德华博士 莫里西，国际知名的肺再生和修复专家，拥有杰出和广阔的 训练记录。此外，一个由互补和多样化的科学家组成的咨询委员会已经 为培训计划提供广度和深度。申请者将从无与伦比的 宾夕法尼亚大学的指导、资源和科学界以及 她的机构。 这项建议的目的是扩大我们对人类未被研究的区域的了解。 肺、呼吸性细支气管。小鼠体内没有呼吸性细支气管，因此它们在肺损伤中起着作用。 再生和修复基本上是未知的，而且经常被忽视。最近的数据表明，呼吸道 细支气管是慢性阻塞性肺疾病的损伤部位，强调了了解分子调控和 在这个生态位内的细胞群体的功能。这个项目最近将研究一种新细胞类型的调节 在人类呼吸性细支气管炎中被鉴定。RASCs可以作为AT2细胞的祖细胞，并且 在COPD中转录改变，表明它们的功能可能在COPD中改变并参与 这种高度流行的疾病的发病机制。这突显了研究这种细胞类型和 它对受伤的反应。这些拟议研究的成功完成将解决以下中心假设 RASCs的细胞命运和祖细胞功能是通过Notch信号和 转录因子Sox4，这一祖细胞功能在COPD中发生了改变。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、下一代测序和高级 原代人肺组织的表观遗传学分析。这些研究将为了解一种新的肺提供重要的见解 并且在治疗慢性阻塞性肺疾病和更广泛的肺再生方面具有很高的潜力。

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.