Illuminating Endocytic Organelles with pH-Resposive [sic] Nanomaterials

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dc.contributor.advisorDeBerardinis, Ralph J.en
dc.contributor.committeeMemberWhite, Michael A.en
dc.contributor.committeeMemberGao, Jinmingen
dc.contributor.committeeMemberDanuser, Gaudenzen
dc.contributor.committeeMemberYoo, Hyuntaeen
dc.contributor.committeeMemberZhong, Qingen
dc.creatorWang, Chensuen
dc.date.accessioned2019-06-03T19:53:35Z
dc.date.available2019-06-03T19:53:35Z
dc.date.created2017-05
dc.date.issued2017-02-20
dc.date.submittedMay 2017
dc.date.updated2019-06-03T19:53:35Z
dc.descriptionPages xvii-xviii are misnumbered as pages xii-xii.en
dc.description.abstractEndosomes, lysosomes and related catabolic organelles are a dynamic continuum of vacuolar structures that impact a number of key cell physiological processes that include protein/lipid metabolism, nutrient sensing and cell survival. To support quantitative investigation of these processes in living cells, we have developed a library of ultra-pH sensitive (UPS) fluorescent nanoparticles with chemical properties that allow fine-scale, multiplexed, spatial-temporal perturbation and quantification of catabolic organelle maturation at single organelle resolution. Deployment in cells enabled quantification of the proton accumulation rate in endosomes; illumination of previously unrecognized regulatory mechanisms coupling pH transitions to endosomal coat protein exchange; discovery of distinct pH thresholds required for mTORC1 activation by free amino acids versus proteins; broad-scale characterization of the consequence of endosomal pH transitions on cellular metabolomic profiles; and functionalization of a context-specific metabolic vulnerability in lung cancer cells. These biological applications benchmarked the robustness and adaptability of this nanotechnology-enabled 'detect and perturb' strategy. As a translational application, we leveraged the technology in high-throughput screening assays that successfully identified chemical agents in the promotion of autophagolysosomal activity through TFEB activation. Formulation of these compounds in liver-tropic biodegradable, biocompatible nanoparticles conferred hepatoprotection against diet-induced steatosis in murine models and prolonged survival in Caenorhabditis elegans. These results highlight the therapeutic potential of small-molecule TFEB activators to ameliorate metabolic syndrome and extend lifespan.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1103324616
dc.identifier.urihttps://hdl.handle.net/2152.5/6595
dc.language.isoenen
dc.subjectEndocytosisen
dc.subjectEndosomesen
dc.subjectFluorescent Dyesen
dc.subjectLysosomesen
dc.subjectNanoparticlesen
dc.titleIlluminating Endocytic Organelles with pH-Resposive [sic] Nanomaterialsen
dc.title.alternativeIlluminating Endocytic Organelles with pH-Responsive Nanomaterialsen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineBiomedical Engineeringen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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