Regulation of MUC19 by Th2 cytokine in airway epithelium

描述(申请人提供)：呼吸道粘液过度生成和上皮性粘液细胞增生/化生是各种呼吸道疾病的临床特征，如COPD、囊性纤维化和哮喘。尽管在这些病变的呼吸道中过量的粘液具有病理学意义，但异常粘液产生的原因和机制在很大程度上尚不清楚。在呼吸道疾病中，我们已经显示了表面气道上皮细胞的“化生”变化，从单独表达“表面”型凝胶形成粘蛋白-MUC5AC到与粘膜下腺特异性MUC5B和我们新发现的一种新的凝胶形成MUC19共同表达。最近，Muc19基因座被证明与唾液腺粘液细胞发育有关。在Muc19基因座有单一突变(SLD)的小鼠，其唾液腺中有粘液细胞缺陷。我们最近发现，含有SLD突变的小鼠的粘膜下腺粘液细胞和Muc19的表达也要少得多。因此，Muc19基因座似乎控制着腺体粘液细胞的发育。重要的是，与长期治疗后被IL-13升高的MUC5AC不同，这种新发现的凝胶形成粘蛋白基因MUC19可以在短期(24小时)内被Th2细胞因子(IL-4和IL-13)刺激。因此，我们推测，Th2细胞因子对MUC19/Muc19的诱导可能是哮喘气道粘液细胞化生过程中一个关键的早期事件，似乎促进了腺体表型的形成。为了验证这一假说，我们提出了四个目标：1)验证MUC19在哮喘呼吸道产生显著增加的假说。2)验证Muc19表达对粘液细胞发育至关重要的假说。2)验证Th2细胞因子在体外转录激活MUC19基因表达的假设。3)在体内验证Th2细胞因子诱导Muc19表达和黏液细胞化生受STAT1和Stat6相互作用调节的假说。该项目的成功将极大地促进我们对Th2细胞因子在上皮粘液过度生产和粘液细胞化生发展中的作用的了解，这将加速开发针对上皮靶向治疗哮喘的药物。

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.