Fetal Lung Development:Role of Wnt5a Signaling

胎儿肺发育：Wnt5a 信号传导的作用

• 批准号: 7430341
• 负责人: CHANGGONG LI
• 金额: $ 30.91万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7430341
• 关键词: Affect; Alveolar; Biological; Birth; Body Size; Cell Communication; Cell Proliferation; Cell physiology; Cells; Cessation of life; Communication; Data; Development; Drosophila genus; Embryonic Development; Epithelial; Family; Fetal Lung; Gene Targeting; Genes; Glycoproteins; Homologous Gene; Lung; Lung diseases; Mediating; Mediator of activation protein; Mesenchymal; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Numbers; Organ; Organogenesis; Pathway interactions; Perinatal; Phenotype; Protein Family; Regulation; Respiratory Insufficiency; Role; SHH gene; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Specificity; Testing; Transgenic Mice; WNT Signaling Pathway; base; beta catenin; cysteine rich protein; loss of function; lung development; member; receptor; response; size

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起重要作用。关于这一通路及其介质在肺形态发生中的作用的信息很少。我们研究了Wnt 5a功能缺失对小鼠肺发育的影响。突变小鼠有多种发育异常，出生后不久死于呼吸功能不全。初步数据表明，Wnt 5a的缺乏导致细胞增殖增加，增强假腺分支形态发生，增加整体肺/身体大小比，但抑制肺泡隔的成熟（增厚的肺泡）。此外，Shh、Ptc、Fgfl 0和Bmp 4的表达在Wnt 5a（-/-）肺中均增加。我们建议： 假设：WNT 5a通过与SHH通路相互作用影响胎肺发育。 三个具体的目标，提出了测试后一种假设。 具体目标1.为了进一步研究Wnt 5a的作用，通过产生和表征SpC：Wnt 5a转基因小鼠。 具体目标2。探讨SHH和WNT信号在肺发育中的相互作用。 具体目标3。目的：研究肺组织中WNT 5a信号通路的受体特异性和细胞内介质。 Wnt 5a的确切作用的表征将有助于我们理解细胞间通讯和肺发育。这些信息将有助于了解先天性和诱导性肺病的分子机制。

项目成果

Ror2 modulates the canonical Wnt signaling in lung epithelial cells through cooperation with Fzd2.

• DOI: 10.1186/1471-2199-9-11
• 发表时间: 2008-01-23
• 期刊: BMC molecular biology
• 作者: Li C;Chen H;Hu L;Xing Y;Sasaki T;Villosis MF;Li J;Nishita M;Minami Y;Minoo P
• 通讯作者: Minoo P