Molecular mechanisms underlying upper airway patterning and tracheomalacia

上呼吸道模式和气管软化的分子机制

• 批准号: 8896856
• 负责人: Debora Sinner
• 金额: $ 11.24万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896856
• 关键词: Address; Advisory Committees; Area; Biology; Caring; Cartilage; Cell Differentiation process; Cell Lineage; Cell Therapy; Cells; Cessation of life; Chondrocytes; Chondrogenesis; Data; Development; Developmental Biology; Disease; Distal; Doctor of Philosophy; Embryo; Endothelial Cells; Environment; Epithelial; Epithelium; Etiology; Fibroblast Growth Factor; Foundations; Funding; Genes; Goals; Histology; Hospitals; In Vitro; Injury; Institutes; Knockout Mice; Knowledge; Ligands; Link; Live Birth; Lung; Mediating; Medical center; Mentors; Mesenchymal; Mesenchyme; Microscopy; Minority; Modeling; Molecular; Molecular Chaperones; Morphogenesis; Mus; Muscle; Muscle Cells; Muscle Development; Mutant Strains Mice; Neonatology; Pattern; Pediatric Hospitals; Pediatrics; Perinatal; Perinatal mortality demographics; Physical condensation; Physiology; Principal Investigator; Public Health; Publishing; Reporting; Reproduction; Research; Research Personnel; Research Training; Resources; Respiratory System; Respiratory tract structure; Role; SHH gene; Scientist; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Actin Staining Method; Source; Symptoms; Technology; Testing; Therapeutic; Trachea; Tracheal Epithelium; Tracheobronchomalacia; Training; Transcriptional Regulation; Transgenic Mice; abstracting; airway epithelium; airway obstruction; career; career development; cartilage development; cell fate specification; congenital anomaly; in vivo; infancy; insight; instructor; mutant; novel; paracrine; post-doctoral training; professor; repaired; transcription factor

DESCRIPTION (provided by applicant): The goal of this application is to provide the minority applicant with additional training that will enable her to become an independent RO1 funded investigator. This investigator completed her PhD in Reproduction of Physiology, a postdoctoral training in Developmental Biology and is currently an instructor in the Division of Pulmonary Biology. During the execution of this project, the principal investigator will acquire expertise in mammalian pulmonary biology, mouse transgenic technology, histology and microscopy. Dr. Jeff Whitsett, Professor of Pediatrics and Director of the Perinatal Institute, will serve as a mentor for the principal investigator. Dr. Whitsett is an internationally recognized leader in the field of Pulmonary Biology. An advisory committee comprise of outstanding scientists, will advise on scientific activities and career development of the principal investigator. This project will be carried out in the Division of Neonatology and Pulmonary Biology at Cincinnati Children's Hospital Medical Center, which is committed to the candidate's academic career and provides an ideal training setting for her development as an independent investigator. The research environment within the division combined with resources across the hospital will maximize the potential for the investigator to establish a scientific niche in pulmonary biology. The research component of this application focuses on the mechanisms by which Wntless, a chaperone dedicated to secretion of Wnt ligands, governs airway morphogenesis. Deletion of Wntless in mouse respiratory tract results in absent tracheal and bronchial cartilaginous rings. Sox9, a master regulator of chondrogenesis, is not detected while the expression domain of Smooth Muscle Actin is expanded. This proposal will test the hypothesis that Wntless induces upper airway patterning by modulation of chondrogenic transcription factor Sox9 via a paracrine mechanism thus promoting differentiation of tracheal mesenchyme. The specific aims are: 1) to define the role of Wntless during tracheal development. This aim will identify Wnt ligands produced by the epithelium and secreted by Wntless. It will also define steps in tracheal chondrogenesis mediated by these ligands. 2) To determine if Wntless is required for cell fate specification of the tracheal mesenchyme. Using cell lineage tracing I will study the cell fate of the tracheal mesenchyme in vivo and I will determine in vitro if Wntless differentially regulates expression of chondrogenic and myogenic genes. 3) To determine the mechanism by which Wntless regulates Sox9 expression. Using embryonic tracheal explant culture I will determine if paracrine canonical or non-canonical signaling controls the expression of Sox9 in tracheal cartilage. These studies will provide critical insights into the poorly understood normal tracheal development and the etiology of tracheomalacia. Understanding how Sox transcription factors are directed by Wnt signaling to promote tracheal cartilage development will lay the foundation for novel cell based therapies to repair damaged or malformed airways. (End of Abstract)

描述（由申请人提供）：本申请的目标是为少数族裔申请人提供额外的培训，使她能够成为一名独立的 RO1 资助的调查员。该研究人员完成了生殖生理学博士学位和发育生物学博士后培训，目前是肺生物学系的讲师。在该项目的执行过程中，主要研究者将获得以下方面的专业知识： 哺乳动物肺部生物学、小鼠转基因技术、组织学和显微镜学。儿科教授兼围产期研究所所长 Jeff Whitsett 博士将担任首席研究员的导师。 Whitsett 博士是肺生物学领域国际公认的领导者。由杰出科学家组成的咨询委员会将为首席研究员的科学活动和职业发展提供建议。该项目将在辛辛那提儿童医院医疗中心的新生儿科和肺生物学科进行，该科致力于候选人的学术生涯，并为她作为独立研究者的发展提供理想的培训环境。该部门内的研究环境与整个医院的资源相结合，将最大限度地发挥研究者在肺生物学领域建立科学定位的潜力。本申请的研究部分重点关注 Wntless（一种致力于分泌 Wnt 配体的分子伴侣）控制气道形态发生的机制。小鼠呼吸道中 Wntless 的缺失导致气管和支气管软骨环缺失。当平滑肌肌动蛋白的表达域扩展时，未检测到软骨形成的主要调节因子 Sox9。该提案将检验以下假设：Wntless 通过旁分泌机制调节软骨形成转录因子 Sox9 来诱导上气道模式，从而促进气管间质的分化。具体目标是：1）明确Wntless在气管发育过程中的作用。该目标将鉴定由上皮产生并由 Wntless 分泌的 Wnt 配体。它还将定义由这些配体介导的气管软骨形成的步骤。 2) 确定气管间充质的细胞命运规范是否需要 Wntless。通过细胞谱系追踪，我将研究体内气管间充质的细胞命运，并在体外确定 Wntless 是否差异调节软骨形成和肌形成基因的表达。 3) 确定Wntless调控Sox9表达的机制。使用胚胎气管外植体培养，我将确定旁分泌规范或非规范信号传导是否控制气管软骨中 Sox9 的表达。这些研究将为人们对正常气管发育和气管软化病因知之甚少提供重要见解。了解 Sox 转录因子如何通过 Wnt 信号传导来促进气管软骨发育，将为修复受损或畸形气道的新型细胞疗法奠定基础。 （摘要完）