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: 7193419
• 负责人: BRIGID L.M. HOGAN
• 金额: $ 36.5万
• 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/7193419
• 关键词: Address; Adult; Alveolus; Asthma; BMP4; Biological Assay; Blood Vessels; Bone Morphogenetic Protein Receptor Gene; Bone Morphogenetic Proteins; Cartilage; Cell Proliferation; Cell model; Cells; Chronic lung disease; Condition; Development; Differentiation and Growth; Disease; Distal; Dose; Embryo; Endoderm; Epithelial; Epithelial Cells; Epithelium; Fibrosis; Gases; Gene Deletion; Gene Expression; Genes; Goals; Growth and Development function; Health; Human; In Vitro; Inflammation; Injury; Interstitial Emphysema; Lead; Life; Ligands; Light; Lung; Lung Inflammation; Lung diseases; Maintenance; Malignant neoplasm of lung; Mediating; Medical; Mesenchymal; Mesenchyme; Mesoderm; Metaplasia; Molecular; Morphogenesis; Mus; Neuroendocrine Cell; Normal Cell; Numbers; Organ; Pathway interactions; Pattern; Phenotype; Play; Population; Premature Infant; Prematurity of fetus; Process; Relative (related person); Research Personnel; Respiratory physiology; Role; Role playing therapy; Signal Pathway; Signal Transduction; Smooth Muscle; Staging; Stem cells; Techniques; Technology; Testing; Therapeutic Intervention; Tissues; Transgenic Organisms; Work; autocrine; base; body system; bone morphogenetic protein receptors; cell type; extracellular; interstitial; loss of function; lung development; mutant; novel therapeutics; paracrine; postnatal; progenitor; protein function; receptor; recombinase; repaired; research study; respiratory smooth muscle; response; response to injury; three dimensional structure; transdifferentiation

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）：肺的正常功能主要取决于许多不同专门细胞类型的正确组织和相互作用。这些包括远端肺泡和近端气道的上皮细胞，以及血管、气道平滑肌和软骨环的间充质细胞。此外，通常存在使成人肺部能够针对炎症和损伤进行重塑和修复的机制。肺部不同细胞类型的增殖、分化和形态发生异常可导致严重的病理状况，包括早产儿慢性肺部疾病、间质纤维化、哮喘和肺癌。该提案的目的是测试关于重要的骨形态发生蛋白（BMP）细胞间信号通路在小鼠肺的发育和出生后重塑中的作用的具体预测。先前的基因表达研究、转基因获得和功能丧失实验以及体外培养测定已经提供了证据，证明编码BMP配体、拮抗剂和受体的基因在肺发育和疾病中发挥着关键作用。然而，许多重要问题仍未得到解答。其中包括 (1) BMP 信号传导通过上皮与间充质中不同受体和配体的精确作用，(2) 不同细胞类型和不同阶段的 BMP 信号传导调节细胞增殖、谱系规范的不同过程的机制、分化和形态发生以及（3）BMP 信号传导在人们知之甚少的出生后肺修复和重塑过程中的作用，这些过程似乎涉及细胞表型的变化（转分化或化生）和祖细胞/干细胞的增殖和分化。我们将使用多种技术来解决这些问题，包括基于 Cre/lox 技术的条件基因删除、正常和突变肺细胞的体外培养以及肺部炎症和损伤模型。总而言之，这些实验将为细胞外信号通路相互作用以控制对人类生命至关重要的器官系统的生长、发育和产后修复的机制提供新的线索。此外，结果将与通过分支形态发生过程发育的其他器官相关。