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Thesis 7-1-18 Tech Edits Bitter Taste Receptor Expression and Function in the Thyroid Item Type dissertation Authors Clark, Adam Austin Publication Date 2014 Abstract The environment is filled with beneficial and harmful compounds. The gustatory system provides a tool to screen them, guiding intake and avoidance. Five human taste perceptions-sweet, sour, bitter, salty, and umami-provide information for this task. ... Keywords T2R; T3; T4; TAS2R; Bitter (Taste); Thyroid Gland Download date 01/10/2021 16:03:30 Link to Item http://hdl.handle.net/10713/4172 Curriculum Vitae Name: Adam A. Clark Degree and Date to be Conferred: Doctor of Philosophy, 2014 Collegiate Institutes Attended: 2009-2014 University of Maryland Baltimore; Baltimore Maryland. Doctor of Philosophy, Toxicology 2014 2006-2008 University of Vermont College of Agriculture and Life Sciences; Burlington, Vermont. Bachelors of Science, Biology 2008 2005-2006 Keene State College; Keene New Hampshire. Undergraduate Studies 2004 University of Colorado Boulder; Boulder, Colorado. Undergraduate Studies Professional Memberships: Association for Chemoreception Sciences Society of Toxicology National Capital Area Chapter Society of Toxicology Publications: Clark AA, Liggett SB, Munger SD. “Extraoral bitter taste receptors as mediators of off- target drug effects”. FASEB J. 2012 Dec;26(12):4827-31. PMID: 22964302 Abstracts: Clark AA, Dotson CD, AET Elson, Steinle NI, Munger SD. “A role of bitter taste receptors in thyroid toxicity and hormone production”. Abstract; Association of Chemoreception Sciences Annual Meeting, 2013 Honors and Awards 2013 Don Tucker Memorial Award for outstanding graduate student presentation, Association for Chemoreception Annual Meeting Clark AA, Dotson CD, AET Elson, Steinle NI, Munger SD. “A role of bitter taste receptors in thyroid toxicity and hormone production”. Abstract; Society of Toxicology National Capital Area Chapter Spring Symposium 2013 Clark AA, Dotson CD, AET Elson, Steinle NI, Munger SD. “A role of bitter taste receptors in thyroid toxicity and hormone production”. Abstract: Society of Toxicology Annual meeting. 2012 Abstract Title of Dissertation: Bitter Taste Receptor Expression and Function in the Thyroid Name: Adam Clark, Doctor of Philosophy, 2014 Dissertation Directed by: Steven D. Munger, PhD., Professor Department of Anatomy and Neurobiology The environment is filled with beneficial and harmful compounds. The gustatory system provides a tool to screen them, guiding intake and avoidance. Five human taste perceptions-sweet, sour, bitter, salty, and umami-provide information for this task. For example, compounds perceived as sweet tasting are highly appetitive, and identify energy rich simple sugars like glucose. Alternatively compounds eliciting the perception of bitterness, an adverse sensation, identify structural motifs associated with toxins. These characteristics outline how taste perceptions help determine the biological impact of the substances in our surroundings. Recent discoveries of taste receptor expression in extraoral tissues, further supports the importance of these receptors. Extraoral taste receptors propagate non-taste associated responses. For example, sweet taste receptors located in entero-endocrine cells of the gut signal for proper utilization of energy rich sugars. By contrast, bitter taste receptors in the upper and lower airways detect irritants and initiate actions helpful in eliminating or reducing pathogens or toxins. Expression of extraoral bitter taste receptors (T2Rs) and their role in recognition and response to toxins has formed the basis of my research, with my thesis focusing on characterization of T2Rs in the human thyroid. My research findings are subdivided into three studies. The first characterized expression of T2Rs in the thyroid using molecular biological analysis and immunohistochemical techniques, which identified mRNA and protein expression of thyroid T2Rs and the taste associated G protein subunit α- gustducin. The second study identified a functional role of thyroid T2Rs utilizing Ca2+ and iodide signaling assays. Stimulation of thyroid cells with various levels of thyroid stimulating hormone (TSH) with or without T2R agonists indicates that bitter-tasting stimuli inhibit TSH-mediated Ca2+ signaling and iodide efflux. The third study aimed to test the effects of T2R agonists on thyroid hormone production in vivo, by assessing changes in mouse thyroxine levels after exposure to T2R agonists. My findings implicate thyroid T2Rs in the regulation of TSH signaling in thyrocytes and suggest that these receptors in turn modulate thyroid hormone production. T2R-mediated thyroid hormone modulation may serve as a protective response to toxin ingestion. Bitter Taste Receptor Expression and Function in the Thyroid By Adam Clark Dissertation submitted to the Faculty of the Graduate School of the University of Maryland, Baltimore in partial fulfillment of the requirements for the degree of Doctor of Philosophy 2014 Acknowledgments I must give a tremendous amount of credit to my mentor Dr. Steven D. Munger. Steve has the uncanny ability to provide valuable and useful information or advice about any question or problem I may have; regardless of the area or topic. Throughout my doctoral studies I have relied heavily on the guidance Steve has given me, both on my thesis project and how to navigate within academic science. I also would like to thank Stephan Vigues. Stephan is a daily resource for every and all questions I may have. I probably ask Stephan at least one question a day. I would also like to thank the members of the Munger lab both past and present that I have had the opportunity to work with. Specifically, thank you Amanda Elson, Kaylin Adipietro, Shawn Dotson, Renee Cockerham, Tatsuyuki Takahashi, Veronica Lopez, Blossom Tewelde, Cedric Uytingco, and Kendra Edwards. Additionally I would like to thank the staff of both the Toxicology Program and The Department of Anatomy and Neurobiology for all their help with logistical matters. Specifically thank you to Linda Horne, Kristi Nichols, Judith Edelman, Leslie Fitzpatrick, and Kathleen Gatchalian. I would also like to thank the members of my committee: Frank Margolis, Iris Lindberg, Kathrine Squibb, and Anil Jaiswal. Thank you for taking the time from your busy schedules to oversee my project and attend my committee meetings. Additionally I would like to thank Wolfgang Meyerhof, Anja Voigt, Ulrich Boehm, and Nanette Steinle for their valuable contributions to my research project. Thank you to my mother Carole and father Ralph Clark for your continuous support and help, and lastly thank you to all the friends I have made over the years both at the University and in the City of Baltimore. iii Table of Contents Acknowledgements............................................................................................................ iv Table of Contents................................................................................................................ v List of Tables..................................................................................................................... x List of Figures.................................................................................................................. xi List of Abbreviations....................................................................................................... xiii 1. An Introduction to the Thyroid 1.1 A Summary of the Thyroid............................................................................... 1 1.1.1 Gross Anatomy of the Thyroid........................................................ 1 1.1.2 Cellular Anatomy of the Thyroid.................................................... 2 1.2 Thyroid Signaling............................................................................................. 4 1.2.1 The Hypothalamic-Pituitary-Thyroid Axis...................................... 4 1.2.2 Thyroid Stimulating Hormone and the Thyroid Stimulating Hormone Receptor.......................................................................... 4 1.2.2a cAMP Signaling................................................................... 5 1.2.2b Ca2+ Signaling..................................................................... 7 1.3 Thyroid Hormone Production......................................................................... 12 1.3.1 Iodide Trafficking............................................................................. 12 1.3.1a NIS and Iodide Uptake....................................................... 12 1.3.1b Pendrin and Iodide Efflux.................................................. 12 1.3.2 Iodide Organification, Triidothyronine, and Thyroxine................... 14 iv 2. An Introduction to Gustation 2.1 A Summary of Gustation................................................................................. 18 2.2 Anatomy of the peripheral gustatory System.................................................. 19 2.2.1 Taste Bud Anatomy........................................................................... 21 2.2.2 Taste Cell Types............................................................................... 22 2.3 Receptors, Ligands, and Peripheral Gustatory Signaling............................... 24 2.3.1 Sweet, Bitter, Umami Receptors....................................................... 24 2.3.1a Sweet Receptors................................................................. 24 2.3.1b Umami Receptors..............................................................
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