Modulation of P-glycoprotein 170 function as a therapeutic target in ulcerative colitis

溃疡性结肠炎是一种常见的慢性炎症性疾病，影响大肠。这种疾病的原因尚不清楚，尽管有强有力的证据表明遗传和环境因素都有影响。目前的治疗是不能令人满意的，依赖于抑制免疫系统的有毒药物。我们实验室最近的研究表明，编码将外来颗粒转运出细胞的泵的基因（MDR-1）的变异可能与引起这种疾病有关。我计划在这个项目中详细研究这一点。我将操纵溃疡性结肠炎小鼠模型和人类肠道细胞中的基因和泵水平，并确定这是否会影响肠道炎症的水平。我将使用最新的基因操作技术来改变基因表达水平，并研究PgP操作后发生的基因变化。这也将为研究PgP如何与肠道防御和免疫系统的其他机制相互作用提供机会。我将测试PgP如何对引起炎症的细菌和化学物质的碎片做出反应。这些实验为UC如何发展提供了可能的新机制，重要的是，为未来治疗的发展提供了基础。

Ulcerative colitis is a common and chronic inflammatory disease affecting the large intestines. The cause of the illness is unknown, although there is strong evidence that both genetic and environmental factors contribute. Current treatment is unsatisfactory, relying on toxic drugs which suppress the immune system. Recently studies from our laboratory suggest that variations in a gene (MDR-1) that codes for a pump that transports foreign particles out of cells might be involved in causing the disease. I plan to study this in detail in this project. I will manipulate the levels of gene and pump levels in mouse models of ulcerative colitis and human gut cells and determine if this influences the level of gut inflammation. I will use the latest gene manipulation technology to change the levels of gene expression and to study gene changes that occurs after PgP manipulation. This will also provide the opportunity to study how PgP interact with other mechanisms of gut defence and the immune system. I will test how PgP respond to fragments of bacteria and chemicals which provoke inflammation. These experiments provide the basis of a possible new mechanism for how UC develops and importantly, the development of a future treatment.