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dc.contributor.advisorPerl, Andras
dc.contributor.authorHuang, Nick
dc.date.accessioned2021-09-13T17:49:08Z
dc.date.available2021-09-13T17:49:08Z
dc.date.issued2020-05-15
dc.identifier.urihttp://hdl.handle.net/20.500.12648/6948
dc.description.abstractEndosomal trafficking is key to intercellular communication and metabolic regulation of immunological development. Rab4a, an endosomal trafficker, is elevated in lupus T cells and polymorphisms of the Rab4a gene have been linked to disease susceptibility. Here, we report the constitutive activation of Rab4a increases susceptibility and severity to lupus nephritis in the genetic SLE1.2.3. model of lupus and is corrected by the deletion of Rab4a in T cells. Alternatively, in a pristane model of induced autoimmunity, the deletion of Rab4a in T cells magnifies the pulmonary manifestations of diffuse alveolar hemorrhage that is otherwise protected by the constitutive activation of Rab4a. Rab4a mediates these changes through control over mTOR, mitochondrial function and homeostasis, and immunological development. In particular, inactivation of Rab4a in T cells reduces expression of activation signals, mitochondrial mass and electrochemical potential. Alterations to Rab4a activity drives the aberrant development and function of anti-inflammatory regulatory T cells and pro-inflammatory double-negative T cells. These data provide new insights into the regulation of metabolism and immunological development through endosomal trafficking. As such, the targeting of Rab4a is a novel therapeutic approach in the treatment of autoimmune diseases such as lupus, which has lacked new targeted therapeutics for more than half a century.en_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectRab4aen_US
dc.subjectSystemic Lupus Erythematosusen_US
dc.subjectmTORen_US
dc.titleRab4acontrol over metabolism and mTOR drives disease progression in Systemic Lupus Erythematosusen_US
dc.typeDissertationen_US
dc.description.versionNAen_US
refterms.dateFOA2021-09-13T17:49:08Z
dc.description.institutionUpstate Medical Universityen_US
dc.description.departmentBiochemistry and Molecular Biologyen_US
dc.description.degreelevelN/Aen_US


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