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

抑制肠道顶端 cAMP/cGMP 转运蛋白 (MRP4) 诱发腹泻

• 批准号: 10408698
• 负责人: Anjaparavanda P Naren
• 金额: $ 37.55万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-20 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408698
• 关键词: Address; Affinity; Agonist; Apical; Applications Grants; Attenuated; Binding; Biopsy; Cell Culture Techniques; Cell membrane; Cells; Complex; Cyclic AMP; Cyclic GMP; Cystic Fibrosis Transmembrane Conductance Regulator; Destinations; Diarrhea; Disease; Epithelial Cells; Fluid Balance; Fluids and Secretions; Gastrointestinal Hormone Receptors; Guanylate Cyclase; Human; In Vitro; Individual; Intestines; Ions; Knockout Mice; Knowledge; Laboratories; Liquid substance; Macromolecular Complexes; Mediating; Modeling; Monitor; Mus; PDZ protein; Pathogenicity; Pathology; Patients; Pharmaceutical Preparations; Production; Proteins; Regulation; Risk; Scaffolding Protein; Seasons; Small Intestines; Testing; Time; Tissues; Transgenic Mice; Travel; Traveler' s diarrhea; assay development; clinically relevant; drug discovery; enterotoxigenic Escherichia coli; enterotoxin STa; enterotoxin receptor; experimental study; gastrointestinal; gastrointestinal epithelium; guanylin; human disease; human model; human stem cells; in vivo; inhibitor; intestinal epithelium; mouse model; multidisciplinary; multiple drug use; novel; pathogen; pathogenic bacteria; protein protein interaction; sodium-hydrogen exchanger regulatory factor; stem cells; uroguanylin

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.

项目摘要 在这个提议中要检验的统一假设是， 鸟苷酸环化酶-C（GC-C）、囊性纤维化跨膜传导调节因子（CFTR）和多药耐药蛋白（MDG）。 药物相关蛋白4（MRP 4）大分子复合物位于或靠近肠质膜 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）和患者来源的肠干细胞， 体外液体分泌。拟议的研究是非常重要的，因为（i）它解决了 通过利用人类和小鼠的模型，研究了几种致命的人类疾病;（ii）它具有临床相关性， 影响;（iii）它是一个多学科项目，涵盖基础生物医学研究，分析开发和使用 个性化的人类干细胞培养