Selective histone deacetlyase inhibition decreases disease in lupus-prone mice

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dc.contributor.authorCastaneda, Adrian Lanceen
dc.contributor.committeechairReilly, Christopher M.en
dc.contributor.committeememberLi, Liwuen
dc.contributor.committeememberLee, Yong Wooen
dc.contributor.committeememberLuo, Xinen
dc.contributor.departmentVeterinary Medicineen
dc.date.accessioned2016-09-16T08:00:18Zen
dc.date.available2016-09-16T08:00:18Zen
dc.date.issued2016-09-15en
dc.description.abstractHistone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that acetylates several proteins that are involved in the immune response. HDAC6 inhibition has been shown in various models to decrease inflammation by altering various proteins involved in the dysregulation of B and T cell responses. In our current studies we sought to determine if HDAC6 inhibition would decrease disease in lupus-prone mice using two murine mouse models of SLE: MRL/lpr mice and NZB/W F1 mice. Both mouse models were fed a rodent diet formulated with the selective HDAC6 inhibitor ACY-738 (N-hydroxy-2-(1-phenylcycloproylamino) pyrimidine-5-carboxamide). NZBW mice received 18 weeks of treatment starting at 16-weeks-of-age and had an average of 57.3 +/- 14.6 ng/mL of ACY-738 in the plasma. MRL/lpr mice received 7 weeks of treatment starting at 11-weeks-of-age and had an average of 78.5 +/- 17.3 ng/mL of ACY-738 in the plasma. Controls received either dexamethasone 5x a week or were left untreated. As the mice aged, body weight, urine protein, and blood sera was collected weekly. Spleen cells were isolated following euthanasia for flow cytometry and kidneys were also collected for histological analyses. We found that in both mouse models that mice treated with ACY-738 had reduced splenic weight and IgG immunoglobulin isotypes. MRL/lpr mice that were treated with ACY-738 had a reduction in the number of IL-17+, ROR-gamma-t TH17 cells. NZBW/ F1 mice that received ACY-738 treatment also had a reduction in the TH17 cells and we observed a significant reduction in kidney pathology. Selective HDAC6 targeting may warrant future investigations as a potential therapeutic target for the treatment of SLE.en
dc.description.degreeMaster of Scienceen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:8802en
dc.identifier.urihttp://hdl.handle.net/10919/72952en
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectSLEen
dc.subjectT cellsen
dc.subjectα -tubulinen
dc.subjectAutoimmunityen
dc.subjectHDACien
dc.subjectHDAC6en
dc.titleSelective histone deacetlyase inhibition decreases disease in lupus-prone miceen
dc.typeThesisen
thesis.degree.disciplineBiomedical and Veterinary Sciencesen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.levelmastersen
thesis.degree.nameMaster of Scienceen

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