The role of sFRP-1 and Wnt as development and repair genes on airway remodeling processes in a mouse model of asthma

哮喘目前是儿童中最常见的慢性疾病，尽管潜在的环境、免疫学和遗传学原理仍然是正在进行的研究的重点。遗传因素和环境因素的相互作用，导致病理性的气道阻塞和结构改变，称为气道重塑，是哮喘发生发展中被广泛接受的基本原理。肺发育研究不仅从胚胎学的角度来看是重要的，而且修复过程通常类似于发育过程，因此需要联合研究努力。肺发育和修复基因不仅在肺损伤后的重建过程中发挥生理学作用，而且与疾病的发展也有关联。目前的项目建议集中在哮喘、呼吸道重塑和肺发育和修复基因之间的关系。主要目的是通过发育中的基因敲除小鼠和哮喘模型，检测其中一组重要的基因，Wnt信号通路及其对SFRP-1的调节作用。初步数据显示，在SFRP-1基因敲除的小鼠和增殖的支气管平滑肌细胞中，一个重要的Wnt途径在哮喘中上调。因此，描述良好的SFRP-1基因敲除小鼠将暴露在慢性哮喘模型中，并将检查侵袭性肺功能参数、组织结构和表达模式。为了将这个项目扩展到Wnt信号通路中涉及的潜在机制问题，它的相互作用和在发育中的作用，Wnt10b基因敲除小鼠将被检测。WNT10b被认为是SFRP-1的配体，因此引起了人们的特别兴趣。他们的肺表型将通过组织学研究、表达模式和定位研究来确定。

Asthma is currently the most common chronic disease among children, although the underlying environmental, immunological and genetic principles are still the focus of ongoing research. The interaction between genetic and environmental factors, which results in a pathological airway obstruction and structural changes known as airway remodeling is the widely accepted basic principle in the development of asthma. Lung development research is not only important from an embryologic point of view, but repair processes often resemble developmental processes and therefore call for a combined research endeavor. Lung development and repair genes are not only known to play a physiological role in restructuring processes after lung injury but have also been associated with the development of diseases. The present project proposal focuses on the relationship between asthma, airway remodeling and lung developmental and repair genes. The main aim is to examine an important group of these genes, the Wnt signaling pathway and its modulating sFRP-1 through knock-out mice in development and in an asthma model. Preliminary data shows an up regulation of one important Wnt pathway for asthma in sFRP-1 knock-out mice and in proliferating bronchial smooth muscle cells. Therefore, well-described sFRP-1-knock-out mice will be exposed to a chronic asthma model and invasive lung function parameters, histological structure and expression patterns will be examined. To extend this project to underlying mechanistical questions involved in the Wnt signaling pathway, its interactions and role in development, Wnt10b-knock-out mice will be examined. Wnt10b has been postulated as a ligand for sFRP-1 and is therefore of special interest. Their lung phenotype will be characterized through histological studies, expression patterns and localization studies.