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" Nicotinamide is a TRPV Channel Agonist in Caenorhabditis elegans and Drosophila melanogaster "
Awani Awani
Hanna-Rose, Wendy
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Latin Dissertation
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| Language of Document
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English
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| Record Number
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804843
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| Doc. No
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TL49679
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1983947135; 10666421
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| Main Entry
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Kalinsky, Joseph Mordechai
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| Title & Author
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Nicotinamide is a TRPV Channel Agonist in Caenorhabditis elegans and Drosophila melanogaster\ Awani AwaniHanna-Rose, Wendy
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| College
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The Pennsylvania State University
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| Date
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2017
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| Degree
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Ph.D.
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| field of study
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Molecular, Cellular, and Integrative Biosciences
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2017
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| Page No
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136
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| Note
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Committee members: Gu, Ying; Lai, Zhi-Chun; Ordway, Richard W.; Rolls, Melissa
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Place of publication: United States, Ann Arbor; ISBN=978-0-355-32963-6
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| Abstract
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Our ability to sense the environment around us and within the body is critical for survival. TRP ion channels are one family of sensory proteins that are implicated in almost every sensory modality i.e., touch, taste, smell, vision, hearing etc. (Islam, 2011). As a result, their dysfunction is implicated in many disease processes making them attractive drug targets (Moran et al., 2011; Nilius and Owsianik, 2010). TRP channels display remarkable diversity during evolution, yet they share many structural and functional similarities among evolutionally diverse species. Model organisms like <i>Caenorhabditis elegans</i> and <i>Drosophila melanogaster</i> provide a tractable system for investigating the complexities of these molecular sensors in a simpler setting. Metabolic regulation of TRP channels is an emerging field (Kahn-kirby et al., 1991; Kumar et al., 2014; Riera et al., 2014). My work reveals role of a form of vitamin B3, Nicotinamide (NAM) in modulating sensory signaling, behaviors and in some cases eliciting cell death via a TRPV channel in <i>C. elegans</i> and <i>D. melanogaster.</i> My lab has established an excellent <i>C. elegans</i> metabolic mutant model <i>pnc-1</i> (pyrazinamidase/nicotinamidase-1) to study how metabolism affects biological processes like development, aging and cell death. I began my research by investigating a cell death phenotype in the <i> pnc-1</i> mutant. Loss of <i>C. elegans</i> nicotinamidase <i> pnc-1</i> that is required for NAD salvage synthesis causes metabolic perturbation and increase in its substrate NAM levels (Vrablik et al., 2009). Four cells in the uterus (uterine-vulval 1 cells) of the animal die due to excess NAM in <i>pnc-1</i> mutant. Here I report that NAM inflicts death on another set of cells found in the head (OLQ neurons) of the animal. I show that the death phenotype is limited to these two cell types because they both express a heteromeric TRPV ion channel made up of OCR-4 and OSM-9 subunits, coexpression of these is necessary for NAM induced cell death. Using electrophysiology in <i>Xenopus</i> oocytes, I determine that NAM is a direct agonist for OCR-4/OSM-9 TRPV ion channel. This is the first successful report of in vitro functional expression any <i>C. elegans</i> TRPV channel. <i>C. elegans</i> TRPV channels are not well characterized and I propose that NAM agonist provides a tool for the same. I further show that NAM agonist activity on TRPV channels is conserved in <i>D. melanogaster. </i> In <i>Drosophila,</i> Nanchung (Nan) and Inactive (Iav) are the OCR- 4 and OSM-9 orthologos respectively. Nan/Iav hetromer is also activated by NAM in electrophysiology in <i>Xenopus</i> oocytes. Calcium imaging in <i>Drosophila</i> larvae shows that NAM application induces a calcium spike and over stimulates the chordotonal neurons (the only cells that co-express Nan/Iav hetromer) and renders them inactive. I also show that behaviors mediated by the orthologous <i>Drosophila</i> channel are responsive to NAM. These results provide an intriguing link between metabolic regulation and TRPV channel activity thus opening avenues for future research.
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| Subject
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Genetics
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| Descriptor
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Biological sciences;C. elegans;Necrosis;Nicotinamide;OLQ cells;TRPV channels;uv1 cells
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| Added Entry
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Hanna-Rose, Wendy
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Molecular, Cellular, and Integrative BiosciencesThe Pennsylvania State University
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