Regulation of MUC19 by Th2 cytokine in airway epithelium

描述（由申请人提供）：气道粘液分泌过多和上皮粘膜细胞增生/化生是与各种气道疾病相关的临床标志，如COPD、囊性纤维化和哮喘。尽管这些病变气道中过量粘液具有病理意义，但异常粘液产生的原因和机制在很大程度上是未知的。我们发现，在气道疾病中，气道表面上皮细胞发生了“化生”变化，从单纯表达“表面”型成胶黏液蛋白muc5ac，到与粘膜下腺特异性MUC5B和MUC19（我们新发现的一种新型成胶黏液）共表达。最近，Muc19基因座已被证明与唾液腺黏液细胞的发育有关。Muc19位点单突变（sld）的小鼠涎腺粘液细胞缺乏。我们最近发现，含有sld突变的小鼠粘膜下腺粘液细胞也少得多，Muc19的表达也少得多。因此，Muc19位点似乎控制腺黏液细胞的发育。重要的是，与MUC5AC在长期治疗后被IL-13升高不同，这个新发现的成胶粘蛋白基因muc19可以在短期内（24小时）被Th2细胞因子（IL-4和IL-13）刺激。因此，我们假设Th2细胞因子诱导MUC19/ MUC19可能是哮喘气道粘膜细胞化生发展的一个关键早期事件，似乎可以促进腺体表型。为了验证这一假设，我们提出了四个目标：1)验证哮喘气道MUC19产生显著升高的假设。2)验证Muc19表达对黏液细胞发育至关重要的假设。2)在体外验证Th2细胞因子转录激活MUC19基因表达的假设。3)在体内验证Th2细胞因子诱导Muc19表达和粘膜细胞化生受Stat1和Stat6相互作用调控的假说。本项目的成功将大大促进我们对Th2细胞因子在上皮粘液过量产生和粘膜细胞化生发展中的作用的理解，这将加速特异性上皮靶向治疗哮喘药物的开发。

DESCRIPTION (provided by applicant): Airway mucus overproduction and epithelial mucous cell hyperplasia/metaplasia are clinical hallmarks associated with various airway diseases, such as COPD, cystic fibrosis and asthma. Despite the pathological significance of the excess mucus in these diseased airways, the cause and the mechanism of the aberrant mucus production is largely unknown. We have shown a "metaplastic" change of surface airway epithelial cells from the sole expression of the "surface" type of gel-forming mucin -MUC5AC to the co-expression with the submucosal gland-specific MUC5B and MUC19, a novel gel-forming we newly discovered, in airway diseases. Most recently, Muc19 locus has been shown to be genetically associated with salivary gland mucous cell development. A mouse having a single mutation (sld) in Muc19 locus shows mucous cell deficiency in their salivary gland. We have recently found that the mouse containing sld mutation also has much less submucosal gland mucous cells and less Muc19 expression. Thus, Muc19 locus appears to control glandular mucous cell development. Importantly, different from MUC5AC, which is elevated by IL-13 after long term treatment, this newly found gel-forming mucin gene-MUC19, can be stimulated by Th2 cytokines (IL-4 and IL-13) in a short-term (24h). Thus, we hypothesize that the induction of MUC19/Muc19 by Th2 cytokine may represent a key early event, seemingly to promote glandular phenotype, in the development of mucous cell metaplasia in asthmatic airway. To test the hypothesis, four aims are proposed: 1) To test the hypothesis that MUC19 production is significantly elevated in asthmatic airway. 2) To test the hypothesis that Muc19 expression is essential for mucous cell development. 2) To test the hypothesis that Th2 cytokine transcriptionally activates MUC19 gene expression in vitro. 3) To test the hypothesis that Th2 cytokine induced Muc19 expression and mucous cell metaplasia are regulated by the interaction of Stat1 and Stat6 in vivo. The success of this project will significantly advance our understanding of Th2 cytokine effect on development of epithelial mucus overproduction and mucous cell metaplasia, which will accelerate the development of specific epithelium-targeting therapeutic agents to treat asthma.