Hedgehog and Platelet-derived growth factor pathway crosstalk in the lung

Hedgehog 和血小板衍生生长因子通路在肺部的串扰

• 批准号: 10242256
• 负责人: Matthias Christian Kugler
• 金额: $ 55.42万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242256
• 关键词: Address; Adult; Alveolar; Alveolar sac; Apoptosis; Attenuated; Binding Sites; Bleomycin; Cell Communication; Cell Count; Cell Proliferation; Cells; Chronic Disease; Cicatrix; Combined Modality Therapy; Communication; Data; Deposition; Development; Disease; Embryo; Epithelial; Epithelium; Erinaceidae; Extracellular Matrix; Feedback; Fibroblasts; Fibrosis; Genetic Transcription; Goals; Grant; Hyperoxia; In Vitro; Individual; Injury; Knock-out; Lung; Mediating; Mesenchymal; Mesenchymal Differentiation; Mesenchyme; Modeling; Molecular; Myofibroblast; Organoids; Pathologic; Pathway interactions; Phenotype; Platelet-Derived Growth Factor; Play; Population; Process; Regulation; Reporter; Research; Role; Signal Pathway; Signal Transduction; Smooth Muscle Actin Staining Method; Testing; Time; Transgenic Organisms; Work; alveolar epithelium; base; cell type; cellular targeting; design; idiopathic pulmonary fibrosis; injured; lung development; lung injury; migration; mortality; overexpression; postnatal; programs; promoter; repaired; response

Summary Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by progressive lung parenchymal scarring. IPF scars are caused by aberrant communication between injured alveolar epithelium and adjacent mesenchyme. Several pathways have been implicated in this communication but the complexity of their intersections has not been fully addressed. We propose that the Hedgehog (HH) and the Platelet-derived growth factor (PDGF) signaling pathways, both of relevance to fibrosis and aberrantly expressed in IPF, conspire to induce progressive scarring. Our goal is to define their interrelationship and to provide a framework for the design of combination therapy to manage this chronic disease for which current treatment options are limited. Our rationale for proposing that the HH and PDGF pathways intersect is based on their shared features and similar functions: i) both HH and PDGF signal from epithelium to mesenchyme; ii) both induce mesenchymal cell proliferation, differentiation and extracellular matrix deposition during lung development; iii) both target myofibroblasts expressing alpha smooth muscle actin (aSMA), a core feature of IPF scars; iv) embryonic overexpression of either pathway produces similar phenotypes; and v) HH inhibition reproduces the key phenotype of Pdgfa and Pdgfra knockout on myofibroblasts during secondary alveolar septum formation, namely simplified alveolar sacs and absent myofibroblasts, accompanied by decreased Pdgfra expression. These data, together with the presence of Gli binding sites in the Pdgfra and Acta2 (aSMA) promoters, indicate vital HH input into PDGFa signaling. The expansion of HH- and PDGFa- mesenchymal responding cells that generate aSMA+ alveolar septal myofibroblasts as well as the presence of aSMA+;Gli1+;PDGFRa+ myofibroblasts in postnatal lung, show these pathways stimulate the same cellular targets and give rise to a common lineage. In adult lung, these same lineages produce myofibroblasts in fibrotic scars, indicating the cellular recipient of HH and PDGFa pathway crosstalk essential for normal development participates in pathological fibrosis. Here we propose to delineate how HH and PDGFa signaling combine to instruct the myofibroblasts, the key cell-type in developing alveolar septa and in fibrosis scars. The central hypothesis is that specific mesenchymal cells integrate HH and PDGFa signaling, and these cells play a pivotal role in processes such as myofibroblast formation during lung development and injury. In Aim 1 we will delineate the molecular mechanisms underlying the HH–PDGF pathway interaction in vitro. In Aim 2 we will determine the role of HH–PDGF crosstalk during postnatal lung development. In Aim 3 we will establish the effect of the combined loss of HH and PDGF signaling in two disease-relevant lung injury models: (1) postnatal hyperoxia and (2) bleomycin-induced injury. This grant will establish the first evidence of HH-PDGFa crosstalk in lung development and lung injury/fibrosis. Our work will provide a roadmap to assess combinations of other pathways that regulate fibrosis.

总结 特发性肺纤维化（IPF）是一种以进行性肺实质瘢痕形成为特征的致死性疾病。 IPF瘢痕是由受损肺泡上皮和邻近肺泡上皮之间的异常通讯引起的。 间充质在这种交流中涉及到几种途径，但它们的复杂性 交叉点尚未得到充分解决。我们建议，刺猬（HH）和血小板衍生的 生长因子（PDGF）信号通路，与纤维化相关，在IPF中异常表达， 会导致疤痕的形成我们的目标是确定它们的相互关系，并提供一个框架， 设计联合治疗来治疗这种慢性疾病，目前的治疗方案是 有限公司我们提出HH和PDGF通路交叉的理由是基于它们的共同特征 和类似的功能：i）HH和PDGF两者都从上皮细胞向间充质细胞发出信号; ii）两者都诱导 肺发育过程中的间充质细胞增殖、分化和细胞外基质沉积; iii） 两者都靶向表达α平滑肌肌动蛋白（aSMA）的肌成纤维细胞，这是IPF瘢痕的核心特征; iv） 任一途径的胚胎过表达产生相似的表型;和v）HH抑制再现了 Pdgfa和Pdgfra基因敲除对继发性肺泡隔形成过程中肌成纤维细胞关键表型， 即简化的肺泡囊和缺失的肌成纤维细胞，伴有Pdgfra表达降低。 这些数据，连同Pdgfra和Acta 2（aSMA）启动子中Gli结合位点的存在，表明 重要的HH输入到PDGFa信号传导中。HH-和PDGFa-间充质应答细胞的扩增， 产生aSMA+肺泡间隔肌成纤维细胞以及存在aSMA+; Gli 1 +;PDGFRa+ 出生后肺中的肌成纤维细胞，显示这些途径刺激相同的细胞靶点， 共同血统在成人肺中，这些相同的谱系在纤维化瘢痕中产生肌成纤维细胞，表明 正常发育所必需的HH和PDGFa通路串扰的细胞受体参与 病理性纤维化在这里，我们提出描述HH和PDGFa信令如何联合收割机来指示 肌成纤维细胞是肺泡隔发育和纤维化瘢痕中的关键细胞类型。核心假设是 特定的间充质细胞整合HH和PDGFa信号，这些细胞在细胞内起着关键作用， 在肺发育和损伤过程中，如肌成纤维细胞的形成。在目标1中， 描述了体外HH-PDGF通路相互作用的分子机制。在目标2中， 确定出生后肺发育过程中HH-PDGF串扰的作用。在目标3中，我们将建立 HH和PDGF信号传导的组合损失在两种疾病相关的肺损伤模型中的作用：（1）出生后 高氧;（2）博莱霉素引起的损伤。这项拨款将建立HH-PDGFa串扰的第一个证据 肺发育和肺损伤/纤维化。我们的工作将提供一个路线图，以评估其他 调节纤维化的途径。