Fetal Lung Development:Role of Wnt5a Signaling

胎儿肺发育：Wnt5a 信号传导的作用

• 批准号: 6921282
• 负责人: CHANGGONG LI
• 金额: $ 32.5万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-12 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6921282
• 关键词: biological signal transduction; cell cell interaction; cell surface receptors; developmental genetics; embryo /fetus; embryogenesis; epithelium; gene expression; genetically modified animals; glycoproteins; histology; intermolecular interaction; laboratory mouse; lung development; morphology; morphometry; newborn animals; protein localization; protein structure function

DESCRIPTION (provided by applicant): Developmental signaling through the wingless/frizzled pathway is an evolutionarily highly conserved mechanism that figures importantly in morphogenesis of many organs. Little information is available regarding the role of this pathway and its mediators in lung morphogenesis. We have examined the consequences of functional deletion of Wnt5a on lung development in mouse. The mutant mice have multiple developmental abnormalities and die shortly after birth with respiratory insufficiency. Preliminary data suggest that absence of Wnt5a results in increased cellular proliferation, enhanced pseudoglandular branching morphogenesis, increased overall lung/body size ration, but inhibits the maturation of the alveolar septa (thickened interstitium). Also, expression of Shh, Ptc, Fgfl0 and Bmp4 are all increased in Wnt5a(-/-) lungs. We propose that: Hypothesis: WNT5a affects fetal lung development through interactions with the SHH pathway. Three Specific Aims are proposed to test the latter hypothesis. Specific Aim 1. To further investigate the role Wnt5a by generating & characterizing SpC: Wnt5a transgenic mice. Specific Aim 2. To determine the interactions of SHH & WNT signaling in lung development. Specific Aim 3. To determine receptor specificity and intracellular mediators of WNT5a pathway in the lung. Characterization of the precise role of Wnt5a will contribute to our understanding of cell-to-cell communication and lung development. This information will be of utility in understanding the molecular mechanisms of congenital and induced lung disease.

描述（由申请人提供）：通过无翅/卷曲途径的发育信号传导是一种进化上高度保守的机制，在许多器官的形态发生中发挥着重要作用。关于该途径及其介质在肺形态发生中的作用的信息很少。我们研究了 Wnt5a 功能性缺失对小鼠肺发育的影响。突变小鼠具有多种发育异常，出生后不久就会因呼吸功能不全而死亡。初步数据表明，Wnt5a 的缺失会导致细胞增殖增加、假腺体分支形态发生增强、肺/身体总体尺寸比增加，但会抑制肺泡隔膜（间质增厚）的成熟。此外，Wnt5a(-/-) 肺中 Shh、Ptc、Fgfl0 和 Bmp4 的表达均增加。我们建议： 假设：WNT5a 通过与 SHH 通路相互作用影响胎儿肺发育。 提出了三个具体目标来检验后一个假设。 具体目标 1. 通过生成和表征 SpC: Wnt5a 转基因小鼠来进一步研究 Wnt5a 的作用。 具体目标 2. 确定 SHH 和 WNT 信号在肺部发​​育中的相互作用。 具体目标 3. 确定肺中 WNT5a 通路的受体特异性和细胞内介质。 Wnt5a 精确作用的表征将有助于我们了解细胞间通讯和肺部发育。这些信息将有助于了解先天性和诱发性肺病的分子机制。