Studies of Bile Acid-Like Signaling Pathways in Mammals and Nematodes

dc.contributor.advisorMangelsdorf, David J.en
dc.creatorZhi, Xiaoyongen
dc.date.accessioned2011-09-30T18:59:50Z
dc.date.available2012-12-01T18:59:50Z
dc.date.issued2010-01-12
dc.description.abstractBile acids are not only detergents for lipid solubilization and absorption, but also important signaling molecules. They regulate biological events in mammals by acting on nuclear receptors and membrane-bound receptors. Bile acid homeostasis is maintained in part through a FXR-SHP signaling circuit, in which SHP functions as a transcriptional corepressor. The mechanism whereby SHP represses was one focus of my thesis research. I used a number of biochemical strategies including tandem affinity purification to identify SHP interacting proteins. I also successfully solubilized SHP recombinant protein, which was used to generate crystals that diffracted to 3.2 Angstroms. Bile acid-like molecules function in nematodes to control a variety of life history traits such as dauer and infective L3 formation through the nuclear receptor DAF-12. Although DAF-12 homologues from different nematode species are functionally and structurally conserved, they show differential pharmacological responses to ligands. To that end, I solved the X-ray crystal structure of the hookworm Ancylostoma ceylanicum DAF-12 ligand binding domain and revealed the molecular basis underlying species specific-ligand binding for DAF-12. Furthermore, DAF-12 was shown to be structurally similar to the bile acid sensor FXR, suggesting bile acid-like signaling pathways have been conserved across evolution. In conclusion, my studies provide new insights into how bile acids are sensed and regulated in mammals and nematodes.en
dc.identifier.oclc761318098
dc.identifier.urihttps://hdl.handle.net/2152.5/919
dc.language.isoenen
dc.subjectBile Acids and Saltsen
dc.subjectReceptors, Cytoplasmic and Nuclearen
dc.subjectHomeostasisen
dc.titleStudies of Bile Acid-Like Signaling Pathways in Mammals and Nematodesen
dc.typeThesisen
dc.type.materialTexten
thesis.date.available2010-12-01
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineBiological Chemistryen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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