Volume Regulatory Pathways in Cystic Fibrosis Mice

囊性纤维化小鼠的容量调节途径

• 批准号: 6460966
• 负责人: WON KYOO CHO
• 金额: $ 6.3万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6460966
• 关键词: cell morphology; chloride channels; cystic fibrosis; disease /disorder model; drug screening /evaluation; gallbladder; gallbladder disorder; gastrointestinal agents; genetically modified animals; ion transport; laboratory mouse; liver disorder; osmotic pressure; potassium channel; secretion; video microscopy; voltage /patch clamp

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is the most common lethal inherited diseases in white population. As CF patients live longer, liver disease has become the second leading cause of death. The development of CF liver disease is believed to result from the secretory defects in the bile ducts leading to the obstructions of bile ductules by tenacious bile secretions, thereby resulting in focal periportal biliary fibrosis/cirrhosis. This explanation in addition to the recent finding that CFTR is only expressed on bile duct cells, but not on hepatocytes, suggest that studying biliary secretion is crucial to understanding the pathophysiology and developing therapeutic strategies for CF liver. By applying the isolation methods developed from rat, recently, novel polarized isolated bile duct unit (IBDU)s have been isolated from normal and CF mice. Therefore, the aims of this research are to further characterize cholangiocytes and IBDU from normal and CF knockout mice, to characterize ion transporters in these cells, and to study the actions and mechanisms of various secretagogues including neuroendocrine peptides in biliary secretion in order to find ways to activate alternative, camp-independent biliary secretory pathways in CF mice. Recent success to isolate IBDU from normal mouse yielded intact polarized functional IBDU that responds to secretin, vasoactive intestinal peptide, and DBcAMP/IBMX. Similar IBDUs were also isolated from CF mice but need further characterization. Recent experiments to study the volume-activated chloride channel as a possible alternative biliary secretory pathway in CF cholangiocytes indicate that cell volume regulation, assessed by regulatory volume decrease (RVD) after hypotonic challenge, is impaired in CF cholangiocytes. Since cell volume regulation is thought to be vital for many cell functions including secretion and ion/substrate transport, this R03 grant is proposing to examine underlying ion transport mechanisms mediating cell volume regulation and their alterations, and to find agent(s) which can correct the impaired cell volume regulation in CF cholangiocytes. Quantitative videomicroscopy will be used to examine the effect of specific inhibitors to ion channels and transporters involved in RVD, and to screen potential agents to correct the impaired RVD of CF mouse cholangiocytes. These promising inhibitors and stimulating agents to ion channels and transporters thus identified will be further investigated by isotope efflux study to examine their effect on Cl-and K+ ion transport, and patch clamping techniques to characterize the ion channels and transporters involved in the RVD. Understanding transport systems and their underlying mechanisms of biliary secretion and cell volume regulation in normal and CF mice will help to formulate therapeutic approaches to overcome the CFTR defect. This project, in turn, will provide the candidate with an excellent opportunity to broaden and develop research and cognitive skills to become independent researcher, the necessary research resources to carry out the proposed research projects, as well as help successfully compete for future research grants.

描述（由申请人提供）：