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dc.contributor.advisorMurphy, George J.en_US
dc.contributor.authorGiadone, Richard Michaelen_US
dc.date.accessioned2020-05-29T13:15:10Z
dc.date.available2020-05-29T13:15:10Z
dc.date.issued2020
dc.identifier.urihttps://hdl.handle.net/2144/41107
dc.description.abstractHereditary transthyretin amyloidosis (ATTR amyloidosis) is a multi-system protein folding disorder that results from >100 described mutations in the transthyretin (TTR) gene. In the disease, non-natively folded TTR, originally produced by the liver, travels throughout circulation and deposits extracellularly at downstream target organs. The multi-tissue etiology of the disease makes it difficult to study in vitro, while no mouse model accurately recapitulates disease pathology. Therefore, we utilized patient-specific induced pluripotent stem cells (iPSCs) to test the hypothesis that production of and exposure to destabilized TTRs results in distinct cellular and molecular changes. The liver’s contribution to the deposition of TTR at distal tissues is understudied. As a result, in Aim 1 we sought to assess the effects of destabilized TTR production on effector hepatic cells. To this end, we utilized gene editing to generate isogenic, patient iPSCs expressing either mutant or wild-type TTR. Combining this tool with single cell RNAseq, we identified hepatic proteostasis factors, including unfolded protein response (UPR) pathways, whose expression coincided with the production of destabilized TTR. Enhancing endoplasmic reticulum (ER) proteostasis within patient hepatic cells via exogenous activation of adaptive UPR signaling, we demonstrated preferential reduction in the secretion of pathogenic TTR. In turn, we demonstrated that production of disease-associated TTR correlates with expression of proteostasis factors capable of regulating TTR secretion and in turn downstream pathogenesis. ATTR amyloidosis patients exhibit extreme phenotypic variation (e.g. TTR fibril deposits at cardiac tissue and/or peripheral nerves). In Aim 2, we sought to define responses of target cell types to pathologically-diverse TTRs. To accomplish this, we profiled transcriptomic changes resulting from exposure to a variety of destabilized TTRs to determine 1) target cell response to TTR exposure and 2) how this response changes across diverse variants and cell types. In doing so, we found that TTR exposure elicits distinct variant- and cell type-specific transcriptional responses. Herein, we addressed our central hypothesis by profiling destabilized TTR production within hepatic cells and TTR exposure at target cell types. Collectively, these data may result in the discovery of unidentified and potentially druggable pathologically-associated pathways for ATTR amyloidosis and other systemic amyloid diseases.en_US
dc.language.isoen_US
dc.rightsAttribution 4.0 Internationalen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCellular biologyen_US
dc.subjectATTR amyloidosisen_US
dc.subjectDisease modelingen_US
dc.subjectInduced pluripotent stem cellsen_US
dc.subjectPersonalized medicineen_US
dc.subjectProtein folding disordersen_US
dc.subjectUnfolded protein responseen_US
dc.titleDefining cellular and molecular mechanisms of hereditary transthyretin amyloidosisen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2020-05-29T04:01:06Z
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplineMolecular and Translational Medicineen_US
etd.degree.grantorBoston Universityen_US
dc.identifier.orcidhttps://orcid.org/0000-0003-4523-3062


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Attribution 4.0 International
Except where otherwise noted, this item's license is described as Attribution 4.0 International