BILE SALT COMPOSITION AND LEVELS IN BILE, SERUM, AND LIVER OF FIC1 MUTANT MICE

FIC1 突变小鼠胆汁、血清和肝脏中的胆汁盐组成和水平

• 批准号: 7724220
• 负责人: LAURA N BULL
• 金额: $ 0.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7724220
• 关键词: Bile fluid; Biological; Biological Assay; Cholates; Cholestasis; Chromosome Mapping; Complex; Computer Retrieval of Information on Scientific Projects Database; Condition; Defect; Development; Disease; Equipment; Etiology; Funding; Genetic; Goals; Grant; Human; Institution; Liver; Mass Spectrum Analysis; Metabolism; Modeling; Mus; Mutant Strains Mice; Mutation; Orthologous Gene; Patients; Phenotype; Predisposition; Protocols documentation; Research; Research Personnel; Resources; Role; Serum; Source; United States National Institutes of Health; Work; bile salts; cholate; design; dietary supplements; mutant; trait

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have identified mutations of FIC1/ATP8B1 as underlying development of cholestasis in some patients. Subsequently, we generated a mouse bearing a mutation in the orthologous gene, as a model of FIC1/ATP8B1 disease. The phenotype of the homozygous Fic1/Atp8b1 mutant mouse differs depending upon background strain. An overall goal of our studies of the Fic1 mutant mouse is to perform genetic mapping to identify genetic modifiers of the murine Fic1 mutant phenotype; such studies will illuminate the biological role of Fic1 and its human ortholog, and may identify candidate susceptibility loci for development and progression of FIC1 disease, as well as more common disorders of complex etiology. To optimize strain choice and protocols for the genetic mapping studies, and to identify those traits for which phenotyping is most worthwhile during those studies, we are further characterizing the phenotypes of Fic1 mutant and wildtype mice of 3 strain backgrounds, after challenge with either control or cholate-supplemented diet. These studies will include analysis of bile salt quantity and composition in bile, serum, and possibly liver; as a fundamental defect in cholestatic disease is in metabolism and transport of bile salts, analysis of bile salts is key to our studies. The UCSF Mass Spectrometry Facility will assist us in this work by providing advice, helping us to design and implement optimal assay conditions, and providing access to the specialized equipment necessary to perform these analyses.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 我们已经确定 FIC1/ATP8B1 突变是某些患者胆汁淤积的潜在发展。 随后，我们培育了一只带有直系同源基因突变的小鼠，作为 FIC1/ATP8B1 疾病的模型。 纯合 Fic1/Atp8b1 突变小鼠的表型因背景菌株而异。 我们对 Fic1 突变小鼠研究的总体目标是进行遗传作图，以确定小鼠 Fic1 突变表型的遗传修饰因子；此类研究将阐明 Fic1 及其人类直向同源物的生物学作用，并可能确定 FIC1 疾病发生和进展的候选易感位点，以及复杂病因学的更常见疾病。 为了优化遗传图谱研究的品系选择和方案，并确定在这些研究中最值得进行表型分析的性状，我们进一步表征了 3 个品系背景的 Fic1 突变体和野生型小鼠在用对照或补充胆酸的饮食。 这些研究将包括分析胆汁、血清以及可能的肝脏中胆汁盐的数量和成分；由于胆汁淤积性疾病的一个基本缺陷是胆汁盐的代谢和运输，因此胆汁盐的分析是我们研究的关键。 加州大学旧金山分校质谱设施将通过提供建议、帮助我们设计和实施最佳分析条件以及提供执行这些分析所需的专用设备来协助我们开展这项工作。