This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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