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

人类远端呼吸道细胞命运和祖细胞功能的分子调控

• 批准号: 10427894
• 负责人: Maria Ciocca Basil
• 金额: $ 16.69万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427894
• 关键词: Address; Advisory Committees; Affect; Alveolar; Area; Award; Bioinformatics; Cell Fate Control; Cell Maintenance; Cell physiology; Cells; Cellular Assay; Cellular biology; Chromatin; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Clinical; Communities; Critical Care; Data; Data Analyses; Development Plans; Disease; Distal; Doctor of Philosophy; Epigenetic Process; Epithelial; Epithelial Cells; Fellowship; Genes; Genetic Transcription; Genomics; Goals; Health; Human; Injury; Institution; International; Knock-out; Knowledge; Lead; Lung; Maintenance; Mentors; Molecular; Molecular and Cellular Biology; Morbidity - disease rate; Mus; Natural regeneration; Oranges; Organ; Pathogenesis; Pathway interactions; Pennsylvania; Population; Regulation; Research; Research Personnel; Resources; Respiratory Disease; Respiratory physiology; Role; SOX4 gene; Scientist; Secretory Cell; Signal Transduction; Site; Structure; Structure of parenchyma of lung; Structure of respiratory bronchiole; Techniques; Testing; Therapeutic; Training; Transcriptional Regulation; Transposase; Universities; University Hospitals; Work; airway epithelium; alveolar epithelium; career; cell type; chronic respiratory disease; clinically relevant; epigenomics; gene regulatory network; genomic data; healing; high resolution imaging; human embryonic stem cell; insight; lung injury; lung regeneration; lung repair; mortality; mouse model; next generation sequencing; notch protein; novel; progenitor; programs; repaired; respiratory; response to injury; self-renewal; skills; small airways disease; stem cell function; stem cell model; stem cells; transcription factor

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.

项目概要/摘要 该提案描述了一个针对独立研究职业发展的五年培训计划 远端气道上皮在人肺损伤和再生中的作用。具体来说，申请人努力 了解一种称为呼吸道分泌的新型人类特定分泌群体的调节 细胞 (RASC)，可以作为肺泡 2 型 (AT2) 细胞的祖细胞，并了解该群体如何 慢性阻塞性肺疾病 (COPD) 发生改变。申请人正处于肺科的最后一年 宾夕法尼亚大学医院的重症监护奖学金，之前接受过细胞领域的博士学位培训 和分子生物学，重点关注细胞命运调控。该奖项的目标是完善和发展技能 作为一名独立研究者，这对于成功的职业生涯是必要的，包括表观基因组学方面的专业知识， 哺乳动物基因编辑和先进的生物信息分析。该奖项的导师是Edward博士 莫里西（Morrisey），国际知名的肺再生和修复专家，具有杰出而广泛的研究经验 培训记录。此外，还成立了一个由互补且多元化的科学家组成的咨询委员会 聚集在一起为培训计划提供广度和深度。申请人将受益于无与伦比的 宾夕法尼亚大学的指导、资源和科学界以及毫无保留的支持 她的机构。 该提案的目的是扩大我们对人类未研究区域的了解 肺，呼吸性细支气管。小鼠中不存在呼吸细支气管，因此它们在肺损伤中发挥作用， 再生和修复本质上是未知的，而且经常被忽视。最近的数据表明，呼吸系统 细支气管是 COPD 的损伤部位，强调需要了解分子调节和 该生态位内细胞群的功能。该项目最近将研究一种新型细胞类型的调控 在人类呼吸细支气管 (RASC) 中发现。 RASC 可以作为 AT2 细胞的祖细胞，并且 COPD 中转录发生改变，表明它们的功能可能发生改变并有助于 这种高度流行的疾病的发病机制。这凸显了研究这种细胞类型和 它对伤害的反应。成功完成这些拟议的研究将解决以下中心假设： RASC 的细胞命运和祖细胞功能通过 Notch 信号传导和 转录因子 SOX4，并且该祖细胞功能在 COPD 中发生改变。这将通过以下方式完成 多种技术，包括人类胚胎干细胞建模、下一代测序和先进的 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 祖细胞，对慢性阻塞性肺病和更广泛的肺再生具有很大的治疗作用。