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，由特化的上皮细胞组成，周围环绕着致密的 间充质网络我们实验室和其他实验室最近的工作表明，空间上的离散 上皮至间充质小生境信号传导是正常肺发育以及成人组织所必需的 静止和再生。这些研究促使我们开发了一种体内通路报告系统， 监测间充质信号通路活性。使用这个报告系统，我们已经解构了 间充质和分类谱系使用创新的方法;单细胞和谱系测序转录组 分析、三维空间定向、体内对损伤的反应和离体生态位支持能力。 我们已经将间充质肺泡小生境细胞（MANC）表征为Wnt应答性的，表达血小板- 衍生的生长因子受体α（PDGFRa），并且对于肺泡上皮细胞生长和自身增殖至关重要。 退款相比之下，Axin 2+肌纤维生成祖细胞（AMP）产生病理上有害的 肌纤维母细胞损伤后。这些研究为确定细胞和分子框架提供了平台 肺间质微生态位。在本提案的目标1中，我将进一步研究血统个体发生 Axin 2阳性间充质的表达，并阐明PDGFRa信号传导在控制谱系分配中的作用， 出生后肺泡形成时期肺泡生态位的发育。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化反应的机制， 急性肺损伤后间质的变化。基于使用多细胞比对的生物信息学分析， 从肺泡生态位的配体和同源受体对，我将定义Notch和Cxcr 4途径的影响 在体内激发AMP谱系的肌纤维化反应。重要的是，该提案概述了一个 严格的培训计划，这将为我在生物医学研究领域的职业发展奠定基础。