MUTLIDRUG RESISTANCE (PGP-170) EXPRESSION IN IBD

多药耐药基因（MDR-1）编码一种基于细胞膜的药物外排泵Pgp-170，该泵在外周血淋巴细胞（pbl）和肠上皮细胞（ECs）表面表达，这些细胞是炎症性肠病（IBD）免疫抑制治疗的假定靶点。对耐多药敲除小鼠的研究表明，高耐多药表达的t淋巴细胞和上皮细胞积极地将糖皮质激素和其他免疫抑制剂运输出靶细胞，从而将其细胞内浓度降低到亚治疗水平。我们之前的研究表明，治疗失败需要直结肠切除术的溃疡性结肠炎患者和需要多次切除难治性疾病的克罗恩病患者与疾病或正常对照相比，PBL MDR表达均显著升高。我们还表明，PBL MDR表达与结肠上皮内淋巴细胞（IEL）和上皮细胞MDR表达相关，并且组成性高淋巴细胞和粘膜MDR表达可能在决定IBD患者对免疫抑制剂治疗的反应中发挥重要作用，特别是糖皮质激素。如果这一假设是正确的，那么评估MDR的表达和功能可能有助于加强IBD患者的药物治疗。在本项目中，我们将专门研究耐多药依赖性糖皮质激素从人t淋巴细胞和肠上皮细胞外排的调节，探索Pgp-170在转运IBD治疗的其他免疫抑制剂中的作用，并评估耐多药泵抑制剂的抗炎功效。

The Multidrug Resistance gene (MDR-1) encodes a cell membrane based drug efflux pump Pgp-170 expressed on the surface of peripheral blood lymphocytes (PBLs) and intestinal epithelial cells (ECs), the putative targets of immunosuppressant therapy in inflammatory bowel disease (IBD). Studies in mdr-knockout mice, indicate that high MDR expressing T-lymphocytes and epithelial cells actively transports glucocorticoids, and other immunosuppressants out of target cells thereby lowering their intracellular concentrations to subtherapeutic levels. Previous work by us has demonstrated that ulcerative colitis patients requiring proctocolectomy for failed medical therapy and Crohn s disease patients requiring multiple resections for refractory disease both showed significantly elevated PBL MDR expression compared to either disease or normal controls. We have also shown that PBL MDR expression correlates with both colonic intraepithelial lymphocyte (IEL) and epithelial cell MDR expression and that constitutively high lymphocyte and mucosal MDR expression may play an important role in determining the response of IBD patients to immunosuppressant therapy, particularly glucocorticoids. If this hypothesis is correct, evaluation of MDR expression and function may be useful in enhancing pharmacotherapy of patients with IBD. In this project we will specifically examine the regulation of MDR-dependent glucocorticoid efflux from human T-lymphocytes and intestinal epithelial cells, explore the role of Pgp-170 in transporting other immunosuppressants central to IBD therapy, and assess the anti-inflammatory efficacy of MDR pump inhibitors.