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Probing Pathways of Innate Immunity Through the Study of Familial Mediterranean Fever.

dc.contributor.authorWaite, Andrea L.en_US
dc.date.accessioned2008-08-25T20:56:27Z
dc.date.availableNO_RESTRICTIONen_US
dc.date.available2008-08-25T20:56:27Z
dc.date.issued2008en_US
dc.date.submitteden_US
dc.identifier.urihttps://hdl.handle.net/2027.42/60829
dc.description.abstractFamilial Mediterranean fever (FMF) is an autoinflammatory disease characterized by self-limiting attacks of fever, pain, and neutrophil influx in the joints, abdomen, chest or skin. FMF is caused by mutations in the Mediterranean Fever locus, which encodes pyrin, a protein expressed primarily in neutrophils and monocytes. Clues as to pyrin’s function have come from our identification of several pyrin-interacting proteins; the further exploration of these interactions have revealed roles for pyrin in the modulation of inflammation through cytoskeletal and apoptotic signaling. First, we establish that pyrin is recruited to regions of actin polymerization by actin, VASP and Arp3, and show that the central region of the pyrin protein is responsible for these interactions. Second, we identify the pro-apoptotic protein Siva as a pyrin binding partner. This interaction involves the C-terminal domain of pyrin and modulates Siva-induced apoptosis. Third, we examine the biology of PSTPIP1, a pyrin binding protein that links PEST-type phosphatases to their substrates. We show that PSTIPIP1 forms membrane-associated tubular filaments that radiate from the center of the cell and establish that an extended Fes-Cip4 homology (EFC) domain of PSTPIP1 is required for this function. Co-expression of pyrin with PSTPIP1 causes a marked change in tubule distribution, an activity that requires the B-box and coiled-coil region of pyrin. Finally, we examine ASC (apoptotic speck-like protein with CARD domain). The pyrin:ASC interaction involves a modified death domain located at the N-terminus of both proteins. ASC forms large cellular aggregates called specks that can act as a platform for inflammation (inflammasome) and/or cell death (pyroptosome). We show that specks prognosticate cell death, and that pyrin modulates speck formation. Treating cells with microtubule toxins dramatically reduces ASC speck aggregation, a finding that could, at least in part, account for the ability of colchicine to ameliorate FMF attacks. In addition, we demonstrate that ASC:pyrin aggregates are remarkably stable in extracellular space, and speculate that they could act to nucleate amyloid, an often fatal complication of FMF. Together, these studies lend new insight into the pathoetiology underlying FMF, and reveal new information about several other inflammatory conditions involving the innate immune system.en_US
dc.format.extent29513214 bytes
dc.format.extent1373 bytes
dc.format.mimetypeapplication/pdf
dc.format.mimetypetext/plain
dc.language.isoen_USen_US
dc.subjectPyrinen_US
dc.subjectFamilial Mediterranean Feveren_US
dc.subjectASCen_US
dc.subjectApoptosisen_US
dc.subjectCytoskeletonen_US
dc.titleProbing Pathways of Innate Immunity Through the Study of Familial Mediterranean Fever.en_US
dc.typeThesisen_US
dc.description.thesisdegreenamePhDen_US
dc.description.thesisdegreedisciplineCell and Developmental Biologyen_US
dc.description.thesisdegreegrantorUniversity of Michigan, Horace H. Rackham School of Graduate Studiesen_US
dc.contributor.committeememberGumucio, Deborah L.en_US
dc.contributor.committeememberFox, David A.en_US
dc.contributor.committeememberKunkel, Steven L.en_US
dc.contributor.committeememberLukacs, Nicholas W.en_US
dc.contributor.committeememberO'Shea, Kathy Sueen_US
dc.contributor.committeememberSwanson, Joel A.en_US
dc.contributor.committeememberVerhey, Kristen J.en_US
dc.subject.hlbsecondlevelMolecular, Cellular and Developmental Biologyen_US
dc.subject.hlbtoplevelScienceen_US
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/60829/1/alhill_1.pdf
dc.owningcollnameDissertations and Theses (Ph.D. and Master's)


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