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dc.contributor.authorPierzchalski, Keely A.
dc.date.accessioned2015-06-29T19:24:28Z
dc.date.available2015-06-29T19:24:28Z
dc.date.issued2015
dc.identifier.urihttp://hdl.handle.net/10713/4600
dc.descriptionUniversity of Maryland, Baltimore. Pharmaceutical Sciences. Ph.D. 2015en_US
dc.description.abstractStatement: A global Rbp1 knock out (Rbp1-/-) mouse model was used to correlate direct retinoid measurements with vitamin A metabolizing and atRA biosynthesizing enzyme activities, Crbp function and tissue microenvironment for the first time. Methods: atRA was quantified by LC-MRM3 and ROL/RE/RAL was quantified by HPLC-UV. Enzyme activities were measured from enzymes present in subcellular fractions isolated from WT and Rbp1-/- tissues. Mouse CrbpI and CrbpIII were purified from transformed Escherichia coli for functional comparative studies. Tissue were formalin fixed for histological examination. Relative gene expression was analyzed using quantitative PCR. Results: Reduced atRA was consistently quantified in extrahepatic tissues with elevated ROL/RE. Relative gene expression showed altered expression in retinoid pathway proteins and atRA loss preceded expression changes in some cases. Tissue microenvironments also consistently showed a loss of structure and organization along with accumulation of extracellular matrix and hyperplasia without apparent disease. Functional studies showed that CrbpIII binds retinol with less affinity than CrbpI and does not function equivalently to CrbpI in regulation of atRA biosynthesis. Also, metabolizing enzymes had altered activities in the Rbp1-/- tissues with reduced atRA biosynthesis. Conclusions: Loss of CrbpI results in altered regulation of enzyme activity and atRA homeostasis cannot be maintained by other Crbp homologs in extrahepatic tissues. Dysfunctional atRA biosynthesis due to loss of CrbpI results in altered tissue microenvironment characteristic of dietary vitamin A deficiency and precancerous dysfunction associated with cancers that are observed to have silenced CrbpI.en_US
dc.language.isoen_USen_US
dc.subjectCrbpIen_US
dc.subjectretinoic aciden_US
dc.subject.lcshBreast--Canceren_US
dc.subject.meshEndometriosisen_US
dc.subject.meshLungen_US
dc.subject.meshTretinoinen_US
dc.subject.meshVitamin Aen_US
dc.titleImpact of cellular retinol-binding protein, type I on retinoic acid biosynthesis and homeostasisen_US
dc.typedissertationen_US
dc.contributor.advisorKane, Maureen A.
dc.description.urinameFull Texten_US
dc.contributor.orcid0000-0002-2456-0382
refterms.dateFOA2019-02-20T20:23:07Z


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