Inhibition of an Apical cAMP/cGMP Transporter(MRP4)in the Gut InducesDiarrhea

项目总结 在这项提案中要检验的统一假设是，由 鸟苷环化酶-C(GC-C)、囊性纤维化跨膜电导调节因子(CFTR)和多个 肠道质膜上或质膜附近的药物相关蛋白-4大分子复合体 上皮细胞调节cGMP介导的分泌性腹泻。我们将使用转基因技术来验证这一假设 小鼠模型(体内研究)和患者来源的隐窝(肠样)来源的肠道干细胞的研究 体液体外分泌。拟议的研究具有非常重要的意义，因为(I)它解决了 几种致命的人类疾病；(Ii)它具有临床相关性和 影响；(Iii)这是一个多学科项目，涵盖基础生物医学研究、分析开发和用途 个性化的人类干细胞培养。

PROJECT SUMMARY The unifying hypothesis to be tested in this proposal is that the compartmentalized regulation mediated by Guanylate Cyclase-C (GC-C), Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Multiple Drug-associated Protein-4 (MRP4) macromolecular complexes at or near the plasma membrane of gut epithelial cells regulates cGMP mediated secretory diarrhea. We will test this hypothesis using transgenic mice model (in vivo studies) and patient derived intestinal stem cells derived from crypts (enteroids) to study fluid secretion in vitro. The proposed studies are highly significant because (i) it addresses the pathologies of several deadly human diseases by utilizing models from humans and mice; (ii) it has clinical relevance and implications; (iii) it is a multidisciplinary project covers basic biomedical studies, assay developments, and uses personalized human stem cell cultures.