Lung Development and Diseases

肺部发育和疾病

• 批准号: 10573209
• 负责人: WEI SHI
• 金额: $ 49.55万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573209
• 关键词: Black race; Bone Morphogenetic Proteins; Cell Differentiation process; Childhood; Cre lox recombination system; Cyst; Cystic Lesion; Defect; Development; Distal; Elastin; Elastin Fiber; Embryo; Enhancers; Environmental Risk Factor; Epithelial Cells; Epithelium; Fetal Lung; Foundations; Future; Gases; Gene Expression; Genetic; Genetic Models; Growth; Growth Factor; Health; Histologic; Human; In Vitro; Intervention; Intracellular Signaling Proteins; Knock-out; Knockout Mice; Ligands; Lung; Lung diseases; Mediating; Mesenchymal; Mesenchyme; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Neonatal; Neonatal Mortality; Organogenesis; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Perinatal mortality demographics; Play; Pregnancy; Prevention strategy; Process; Production; Respiratory Disease; Role; Signal Pathway; Signal Transduction; Signaling Protein; Smooth Muscle Myocytes; Structure; Study models; System; Transcription Coactivator; Transgenic Organisms; airway epithelium; bone morphogenetic protein receptors; cell growth; fetal; human disease; in vivo; lung development; malformation; mortality; mouse genetics; mouse model; neonatal morbidity; novel; prenatal; progenitor; respiratory smooth muscle; surfactant production; therapy development; tool

Project Summary/Abstract Abnormal lung development results in a variety of congenital respiratory diseases contributing to neonatal morbidity and mortality. Although BMP signaling is known to be important in lung organogenesis, understanding of BMP in lung development and pulmonary diseases is incomplete. In particular, BMP signaling in developing lung mesenchyme has not been studied due to embryonic lethality in mice with global abrogation of BMP pathway and the lack of genetic tools to target lung mesenchyme. Using our new Tbx4 lung enhancer- driven loxP/Cre system, lung mesenchymal BMP receptor IA (Bmpr1a) has been specifically deleted. The knockout mice have abnormal airway branching and cystic malformation, which resembles the pathology of congenital pulmonary airway malformation seen in human patients. Deficiencies of airway smooth muscle cells and subepithelial elastin fibers, abnormal mesenchymal expression of Bmp ligands, as well as airway epithelial perturbation of Sox2-Sox9 progenitor axis are found in the cystic lungs of the Bmpr1a knockout mice. In addition, we found that Bmpr1a-mediated Smad-independent signaling regulated airway smooth muscle cell growth and elastin expression in vitro and in vivo. Thus, we hypothesize that mesenchymal Bmpr1a-mediated Smad-independent signaling is essential for airway smooth muscle cell differentiation and subepithelial elastin production as well as suppression of Bmp ligand expression. Combined disruption of these processes results in abnormal airway development and subsequent prenatal airway cystic malformation. Two specific aims are proposed: (1) To determine the pathogenic mechanisms by which defective mesenchymal BMP signaling causes congenital lung malformation through disruption of the airway smooth muscle and subepithelial elastin layer. Mesenchymal Bmpr1a will be deleted in embryonic mouse lung. The lung mesenchymal abnormality and its contribution to airway cystic malformation will be determined from histologic structure to cellular and molecular changes. The underlying molecular mechanisms from BMP intracellular signaling (Smad- independent pathway) to decreased Myocd expression/SMC differentiation and deficiency of subepithelial elastin production will then be studied using both in vivo and in vitro approaches. (2) To determine the mechanisms by which mesenchymal deficiency of Bmpr1a indirectly results in abnormal airway epithelial growth and overall airway abnormality. The airway epithelial abnormality resulting from mesenchymal Bmpr1a deletion will be analyzed. The mechanisms by which mesenchymal deficiency of Bmpr1a signaling results in abnormal mesenchymal-epithelial crosstalk through mesenchymal misexpression of Bmp ligands will be studied. The role of the resultant airway epithelial Sox2+ progenitor deficiency and Sox9+ progenitor expansion in contributing to the lung abnormality will also be investigated.

项目总结/摘要 肺发育异常导致多种先天性呼吸道疾病， 发病率和死亡率。虽然已知BMP信号传导在肺器官发生中是重要的， 对BMP在肺发育和肺部疾病中的作用的了解还不完全。尤其是BMP信号 在发育中的肺间充质中，由于小鼠的胚胎致死性， BMP通路的缺陷和缺乏靶向肺间质的遗传工具。使用我们新的Tbx 4肺增强剂- 在loxP/Cre系统驱动下，肺间充质BMP受体IA（Bmpr 1a）被特异性缺失。的 基因敲除小鼠具有异常的气道分支和囊性畸形，这类似于 先天性肺气道畸形在人类患者中观察到。气道平滑肌细胞防御 和上皮下弹性蛋白纤维，Bmp配体的异常间质表达，以及气道上皮细胞 在Bmpr 1a敲除小鼠的囊性肺中发现了Sox 2-Sox 9祖细胞轴的扰动。在 此外，我们发现Bmpr 1a介导的Smad非依赖性信号调节气道平滑肌细胞 体外和体内的生长和弹性蛋白表达。因此，我们假设间充质Bmpr 1a介导的 Smad非依赖性信号对气道平滑肌细胞分化和上皮下弹性蛋白至关重要 产生以及抑制BMP配体表达。这些过程的综合破坏导致 异常气道发育和随后的产前气道囊性畸形。两个具体目标是 提出：（1）确定间充质BMP信号缺陷的致病机制， 通过破坏气道平滑肌和上皮下弹性蛋白导致先天性肺畸形 层.间充质Bmpr 1a将在胚胎小鼠肺中缺失。肺间质异常， 它对气道囊性畸形的作用将从组织学结构到细胞和 分子变化BMP细胞内信号传导（Smad-1）的潜在分子机制 独立途径）降低Myocd表达/SMC分化和缺乏上皮下 然后将使用体内和体外方法研究弹性蛋白的产生。(2)确定 Bmpr 1a间充质缺陷间接导致气道上皮细胞异常的机制 生长和整体气道异常。间充质Bmpr 1a导致的气道上皮异常 将分析删除。Bmpr 1a信号转导的间充质缺陷导致 通过BMP配体的间充质错误表达的异常间充质-上皮串扰将是 研究了气道上皮Sox 2+祖细胞缺陷和Sox 9+祖细胞扩增的作用 也将研究导致肺部异常的因素。