Regulation of MUC19 by Th2 cytokine in airway epithelium

描述（由申请方提供）：气道粘液过度产生和上皮粘液细胞增生/化生是与各种气道疾病（如COPD、囊性纤维化和哮喘）相关的临床标志。尽管这些患病气道中的过量粘液的病理学意义，但异常粘液产生的原因和机制在很大程度上是未知的。我们已经显示了表面气道上皮细胞的“化生”变化，从“表面”类型的凝胶形成粘蛋白MUC 5AC的单独表达到与粘膜下腺体特异性MUC 5 B和MUC 19的共表达，MUC 19是我们在气道疾病中新发现的一种新的凝胶形成。最近，Muc 19基因座已被证明与唾液腺粘液细胞发育的遗传相关。在Muc 19基因座中具有单一突变（sld）的小鼠在其唾液腺中显示粘液细胞缺乏。我们最近发现，含有sld突变的小鼠也具有更少的粘膜下腺体粘液细胞和更少的Muc 19表达。因此，Muc 19基因座似乎控制腺粘液细胞的发育。重要的是，与长期治疗后IL-13升高的MUC 5AC不同，这种新发现的凝胶形成粘蛋白基因MUC 19可以在短期（24小时）内被Th 2细胞因子（IL-4和IL-13）刺激。因此，我们假设MUC 19/Muc 19的诱导Th 2细胞因子可能代表一个关键的早期事件，似乎促进腺体表型，在哮喘气道粘液细胞化生的发展。为了验证这一假设，我们提出了四个目标：1）验证哮喘气道中MUC 19产生显著升高的假设。2)为了验证Muc 19表达对粘液细胞发育至关重要的假设。2)验证Th 2细胞因子在体外转录激活MUC 19基因表达的假设。3)目的：验证Th 2细胞因子诱导的Muc 19表达和粘液细胞化生受Stat 1和Stat 6相互作用调节的假说。该项目的成功将显著促进我们对Th 2细胞因子在上皮粘液过度产生和粘液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剂的开发以治疗哮喘。

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.