BMP Signaling in Lung Development and Postnatal Repair

BMP 信号在肺发育和产后修复中的作用

• 批准号: 6908520
• 负责人: BRIGID L.M. HOGAN
• 金额: $ 38.5万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908520
• 关键词: biological signal transduction; bone morphogenetic proteins; cell differentiation; cell proliferation; gene deletion mutation; genetically modified animals; in situ hybridization; inflammation; laboratory mouse; lung development; lung injury; mesenchyme; protein structure function; regeneration; respiratory epithelium; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): The normal functions of the lung depend critically upon the correct organization and interaction of many different specialized cell types. These include the epithelial cells of the distal alveoli and proximal airways, and the mesenchymal cells of the blood vessels, airway smooth muscle and cartilage rings. In addition, mechanisms normally exist that enable the adult lung to undergo remodeling and repair in response to inflammation and injury. Abnormalities in the proliferation, differentiation and morphogenesis of the different cell types of the lung can lead to serious pathological conditions, including chronic lung disease of premature babies, interstitial fibrosis, asthma and lung cancer. The goal of this proposal is to test specific predictions about the roles of the important Bone Morphogenetic Protein (BMP) intercellular signaling pathway in the development and postnatal remodeling of the mouse lung. Previous gene expression studies, transgenic gain and loss-of-function experiments, and in vitro culture assays have provided evidence that genes encoding BMP ligands, antagonists, and receptors play critical roles in lung development and disease. However, many important questions remain unanswered. Among these are (1) the precise roles of BMP signaling through different receptors and ligands in the epithelium versus the mesenchyme, (2) the mechanisms by which BMP signaling in different cell types and at different stages regulates distinct processes of cell proliferation, lineage specification, differentiation and morphogenesis and (3) the role of BMP signaling in the poorly understood processes of postnatal lung repair and remodeling that appear to involve both changes in cell phenotype (transdifferentiation or metaplasia) and the proliferation and differentiation of progenitor/stem cells. We will address these questions using a variety of techniques, including conditional gene deletion based on Cre/lox technology, in vitro culture of normal and mutant lung cells and models of lung inflammation and injury. Taken together, these experiments will throw new light on the mechanisms by which extracellular signaling pathways interact to control the growth, development and postnatal repair of an organ system that is essential for human life. Moreover, the results will be relevant to other organs that develop by the process of branching morphogenesis.

描述（由申请人提供）：肺的正常功能严重取决于许多不同专用细胞类型的正确组织和相互作用。其中包括远端肺泡和近端气道的上皮细胞，以及血管的间充质细胞，气道平滑肌和软骨环。此外，通常存在使成年肺对炎症和损伤进行重塑和修复的机制。肺的不同细胞类型的增殖，分化和形态发生异常会导致严重的病理状况，包括早产婴儿的慢性肺疾病，间质性纤维化，哮喘和肺癌。该提案的目的是测试有关重要骨形态发生蛋白（BMP）的细胞间信号传导途径在小鼠肺发育和产后重塑中的特定预测。先前的基因表达研究，转基因的增益和功能丧失实验以及体外培养试验提供了证据，表明编码BMP配体，拮抗剂和受体的基因在肺发育和疾病中起着至关重要的作用。但是，许多重要的问题仍未得到解决。其中包括（1）BMP信号通过上皮中与间质的不同受体和配体的精确作用，（2）（2）在不同细胞类型中BMP信号传导以及在不同阶段调节不同阶段的BMP信号的机制，可以调节细胞增殖的不同过程，谱系扩增，谱系规范，差异化，分化和形成的过程（3）BMP的作用（3）在BMP的作用中，该作用是BMP的作用。重塑似乎涉及细胞表型的变化（转分化或化生）以及祖细胞/干细胞的增殖和分化。我们将使用各种技术解决这些问题，包括基于CRE/LOX技术的条件基因缺失，正常和突变肺细胞的体外培养以及肺部炎症和损伤的模型。综上所述，这些实验将对细胞外信号通路相互作用以控制器官系统的生长，发育和产后修复的机制进行新的启示。此外，结果将与通过分支形态发生过程发展的其他器官有关。