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dc.contributor.advisorFarrar, J. Daviden
dc.creatorZlatkov, Clare Marieen
dc.date.accessioned2016-09-01T19:26:09Z
dc.date.available2016-09-01T19:26:09Z
dc.date.created2014-08
dc.date.issued2014-07-17
dc.date.submittedAugust 2014
dc.identifier.urihttps://hdl.handle.net/2152.5/3584
dc.description.abstractRetinol plays a vital role in the immune response to infection, however it remains unclear which proteins mediate retinol transport during infection. Serum amyloid A (SAA) proteins are produced by the liver following acute systemic infection and are also induced by bacteria in the intestine. SAAs have been proposed to play a role in the inflammatory response to infection and injury, but their exact functions have not been well defined. In this dissertation, I present data that demonstrates the acute phase protein SAA is a novel retinol binding protein that transports retinol during infection. SAA proteins are induced by bacteria and additionally require retinol for their expression. I demonstrate that SAA’s requirement for retinol is not restricted to the small intestine, as mice on a vitamin A deficient diet have reduced SAA expression in the liver as well. Additionally, I demonstrate in fluorescence based binding assays that SAAs are capable of binding retinol at nanomolar affinities, which is comparable to a known retinol binding protein. I also found that SAA proteins associate with retinol in the serum following a bacterial challenge in wild-type mice. This phenotype was not observed in SAA1/2-/- mice following bacterial challenge. Furthermore, SAA1/2-/- mice have greater bacterial loads in their spleens and livers following bacterial infection. In parallel with my studies, Dr. Mehabaw Derebe, a post-doctoral researcher in the Hooper lab, recently solved the mSAA3 crystal structure, demonstrating the protein oligomerizes to form a tetramer. This tetramer unit contains a central pore-like cavity, lined with hydrophobic amino acid residues, which would allow a lipophilic ligand to bind. A single amino acid mutation within this hydrophobic core resulted in reduced mSAA3 retinol binding. This structural insight describes how SAA, as a small and mostly alpha-helical protein, can protect a lipophilic ligand from the aqueous environment. Altogether, these data demonstrated that SAAs are a family of microbe-induced retinol binding proteins, reveal a unique protein architecture involved in retinol binding, and provide insight into the acute response to infection.en
dc.format.mimetypeapplication/pdfen
dc.language.isoenen
dc.subjectRetinol-Binding Proteinsen
dc.subjectSalmonella Infectionsen
dc.subjectSerum Amyloid A Proteinen
dc.subjectVitamin Aen
dc.titleSerum Amyloid A is a Retinol Binding Protein that Transports Retinol during Bacterial Infectionen
dc.typeThesisen
dc.date.updated2016-09-01T19:09:28Z
dc.type.materialtexten
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.nameDoctor of Philosophyen
thesis.degree.levelDoctoralen
thesis.degree.disciplineImmunologyen
dc.contributor.committeeMemberHooper, Lora V.en
dc.contributor.committeeMemberKliewer, Steven A.en
dc.contributor.committeeMemberPasare, Chandrashekharen
dc.identifier.oclc957676369


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