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: 10473820
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10473820
• 关键词: 3-Dimensional; AGTR2 gene; Acute Lung Injury; Address; Adult; Affect; Alveolar; Alveolus; Architecture; Asthma; Bioinformatics; Biomedical Research; CXCR4 gene; Cell Lineage; Cell Surface Receptors; Cells; Cellular biology; Chronic Disease; Chronic Obstructive Pulmonary Disease; Complex; Data; Databases; Development; Disease; Epithelial; Equilibrium; Exhibits; Fibrosis; Foundations; Gases; Genetic; Growth; 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 health; 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 肺是一种结构复杂的器官，由专门的上皮细胞组成，周围是密集的 间质网络。我们实验室和其他实验室的最新工作表明，空间谨慎 适当的肺发育以及成年组织需要上皮到间充质的小众信号传导 静止和再生。这些研究促使我们开发了一个体内途径记者系统 监视间充质信号通路活动。使用此记者系统，我们已经解构了 使用创新方法的间充质和分类谱系；单细胞和谱系seq转录组 分析，三维空间取向，在体内对损伤和离体利基支持能力的反应。 我们已经表征了间充质肺泡细胞（MANC）的wnt响应，表达了血小板 衍生的生长因子受体α（PDGFRA），对于肺泡上皮细胞生长和自我至关重要 更新。相反，AXIN2+肌原祖细胞（AMP）细胞产生病理上有害的 受伤后的肌纤维细胞。这些研究为定义细胞和分子框架提供了一个平台 肺间充质壁ni。向前迈进，在该提案的目标1中，我将检查谱系个体的个体发育 AXIN2阳性间充质的构造，并阐明了PDGFRA信号在控制谱系分配和 肺泡后期期间肺泡生态位的发展。在独立阶段 在AIM 2概述的 急性肺损伤后的间充质。基于生物信息学分析，使用多细胞对齐 我将定义Notch和CXCR4途径的影响，配体和同源受体对 在引起体内AMP谱系的肌能反应时。重要的是，该提议概述了 严格的培训计划将建立基础，以推动我在生物医学研究领域的职业。