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: 10210771
• 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/10210771
• 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; Epithelium; 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; 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 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