The roles of Inturned in mammalian lung development

项目摘要 先天性肺畸形（CLM）是一系列罕见的出生缺陷，在最严重的情况下是致命的出生。 这些缺陷的有效预防和早期干预需要全面了解其机制 是胚胎肺形态发生的基础。PI发现小鼠胚胎的CPLANE（纤毛）突变 和平面极性效应子）蛋白Intu在胚胎的生长和气道分支中表现出严重的缺陷， 肺PI将检验以下假设：Intu缺失导致纤毛形成严重缺失，因此纤毛受损- 依赖Hh和PDGF信号传导。他将研究Intu的缺失是否会影响体内Hh和PDGF通路的输出 以及肺组织对培养的Shh和PDGF的反应。他还将测试Intu和一个 肺形态发生中Hh通路的关键调节因子Gli 2。随后，他将研究Intu突变对 通过候选基因方法在胚胎肺发育中的信号通路和组织模式，其中 将检查已知的肺发育调节剂。他随后将研究Intu突变是否改变了 肺发育中的细胞增殖和程序性细胞死亡。最后，PI将采用转录组学方法， 比较野生型和Intu突变型肺之间的转录谱。拟议的研究将揭示作用 CPLANE蛋白和纤毛在胚胎肺发育中的作用，并有助于更好地了解肺部疾病 例如CLM。

Project Summary Congenital Lung Malformation (CLM) is a series of rare birth defects that in the most severe case are fatal at birth. The effective prevention and early intervention of these defects require a comprehensive understanding of the mechanisms underlying the morphogenesis of the embryonic lungs. The PI found that mouse embryos mutant for the CPLANE (cilia and planar polarity effector) protein Intu exhibited severe defects in the growth and airway branching of the embryonic lungs. The PI will test the hypothesis that loss of Intu leads to severe loss of cilia formation, hence compromised cilia- dependent Hh and PDGF signaling. He will examine whether loss of Intu affects Hh and PDGF pathway outputs in vivo and the response of the lung tissue to Shh and PDGF in culture. He will also test the genetic interaction between Intu and a key regulator of Hh pathway, Gli2, in lung morphogenesis. Subsequently, He will examine the impact of Intu mutation on signaling pathways and tissue patterning in embryonic lung development through a candidate gene approach, in which known regulators of lung development will be examined. He will subsequently examine whether Intu mutation alters the proliferation and programmed cell death in lung development. Finally, the PI will take a transcriptomics approach, to compare the transcriptional profiles between wild type and Intu mutant lungs. The proposed research will reveal the roles of CPLANE proteins and cilia in embryonic lung development, and contribute to the better understanding of lung diseases such as CLM.