Defining the molecular determinants of mesenchymal lineage allocation in lung development and disease

定义肺发育和疾病中间充质谱系分配的分子决定因素

• 批准号: 10247829
• 负责人: Jarod Zepp
• 金额: $ 24.9万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247829
• 关键词: 3-Dimensional; AGTR2 gene; Acute Lung Injury; Address; Adult; Affect; Alveolar; Architecture; Asthma; Bioinformatics; Biomedical Research; CXCR4 gene; Cell Lineage; Cell Surface Receptors; Cells; Cellular biology; Chronic Disease; Chronic Obstructive Airway Disease; Complex; Data; Databases; Development; Disease; Epithelial; Equilibrium; Exhibits; Fibrosis; Foundations; Gases; Genetic; Growth; Health; Heterogeneity; Injury; Investigation; Knock-out; Knowledge; Ligands; Lung; Lung diseases; Malignant neoplasm of lung; Maps; Mesenchymal; Mesenchymal Differentiation; Mesenchymal Stem Cells; Mesenchyme; Methods; Modeling; Molecular; Monitor; Mus; Myofibroblast; NOTCH3 gene; Natural regeneration; Normal tissue morphology; Organ; Outcomes Research; Paracrine Communication; Pathogenicity; Pathologic; Pathway interactions; Phase; Platelet-Derived Growth Factor alpha Receptor; Population; Process; Pulmonary alveolar structure; Regenerative capacity; Regenerative response; Regulation; Reporter; Research; Role; Scientist; Signal Pathway; Signal Transduction; Space Perception; Spatial Distribution; Specialized Epithelial Cell; Stromal Cells; System; Testing; Therapeutic; Tissues; Training; Work; alveolar epithelium; base; career; cell growth; cell type; epithelium regeneration; experimental study; gain of function; idiopathic pulmonary fibrosis; in vivo; innovation; insight; interstitial; lung development; lung regeneration; notch protein; outcome prediction; postnatal period; progenitor; receptor; receptor expression; regenerative; respiratory smooth muscle; response; response to injury; self-renewal; stem cells; tissue injury; tissue repair; tissue-repair responses; transcriptome

PROJECT ABSTRACT The lung is an architecturally complex organ, comprised of specialized epithelial cells surrounded by a dense network of mesenchyme. Recent work from our lab as well as others has shown that spatially discreet epithelial to mesenchymal niche signaling is required for proper lung development as well as adult tissue quiescence and regeneration. These studies prompted us to develop an in vivo pathway reporter system to monitor mesenchymal signaling pathway activity. Using this reporter system, we have deconstructed the mesenchyme and classified lineages using innovative methods; Single-Cell and Lineage-Seq transcriptome profiling, three-dimensional spatial orientation, in vivo response to injury and ex vivo niche support capacity. We have characterized a mesenchymal alveolar niche cell (MANC) as Wnt responsive, expresses platelet- derived growth factor receptor alpha (PDGFRa), and is critical for alveolar epithelial cell growth and self- renewal. In contrast, the Axin2+ myofibrogenic progenitor (AMP) cell generates pathologically deleterious myofibroblasts after injury. These studies provide a platform for defining the cellular and molecular framework of the lung mesenchymal niches. Moving forward, in Aim 1 of this proposal, I will examine the lineage ontogeny of Axin2-positive mesenchyme and elucidate the role of PDGFRa-signaling in controlling lineage allocation and development of the alveolar niche during the postnatal period of alveologenesis. In the independent phase outlined in Aim 2, I will define mechanisms controlling the pro-regenerative versus myofibrogenic responses in the mesenchyme after acute lung injury. Based on bioinformatic analyses using multicellular alignment of ligand and cognate receptor pairs from the alveolar niche, I will define the impact of Notch and Cxcr4 pathways in provoking the myofibrogenic response from the AMP lineage, in vivo. Importantly, this proposal outlines a rigorous training plan that will establish the foundation to advance my career in biomedical research.

项目摘要 肺是一个结构复杂的器官，由特殊的上皮细胞组成，周围有致密的 间质网络。我们实验室和其他实验室最近的工作表明，空间上离散 上皮到间充质生态位信号传导是肺和成人组织正常发育所必需的 静止和再生。这些研究促使我们开发一种体内途径报告系统 监测间充质信号通路活性。使用这个报告系统，我们解构了 使用创新方法进行间充质和分类谱系；单细胞和谱系测序转录组 分析、三维空间方向、体内对损伤的反应和离体生态位支持能力。 我们已将间充质肺泡微环境细胞 (MANC) 表征为 Wnt 反应性、表达血小板- 衍生生长因子受体α（PDGFRa），对于肺泡上皮细胞生长和自我修复至关重要 更新。相反，Axin2+肌纤维化祖细胞（AMP）产生病理学上有害的 受伤后的肌成纤维细胞。这些研究为定义细胞和分子框架提供了一个平台 肺间质微生境。展望未来，在本提案的目标 1 中，我将研究谱系个体发育 Axin2 阳性间充质的形成并阐明 PDGFRa 信号在控制谱系分配和 出生后肺泡发生期间肺泡生态位的发育。在独立阶段 在目标 2 中概述，我将定义控制促再生与肌纤维形成反应的机制 急性肺损伤后的间质。基于使用多细胞比对的生物信息学分析 来自肺泡生态位的配体和同源受体对，我将定义 Notch 和 Cxcr4 途径的影响 在体内激发 AMP 谱系的肌纤维化反应。重要的是，该提案概述了 严格的培训计划将为我在生物医学研究领域的职业发展奠定基础。