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  • Jessica Tanis, Ph.D. ,

    Assistant Professor

    Assistant Professor

    (302) 831-8439

    Biography

    Calcium homeostasis modulator 1 (CALHM1) is an ion channel expressed in the brain and taste buds that plays important roles in cultured cortical neuron excitability and taste perception. Human genetic studies suggest that the P86L polymorphism in CALHM1 accelerates late onset Alzheimer’s disease onset, however, the physiological significance of CALHM1 activation in the mammalian brain remains unclear. CALHM1 and its C. elegans homolog, CLHM-1, exhibit similar biophysical properties when expressed in Xenopus oocytes and functional conservation when expressed in C. elegans. We are utilizing the anatomical simplicity, genetic tools, and easily quantifiable behaviors of C. elegans to define CLHM-1 function.

    Our study of C. elegans CLHM-1 has resulted in the development of diverse projects. Using a combination of genetic, imaging, behavioral, electrophysiological, and biochemical approaches members of my lab are seeking to 1) understand mechanisms underlying extracellular vesicle formation and cargo sorting, 2) identify regulators of CLHM-1 function, 3) understand the role of diet in amyloid-beta toxicity, 4) characterize novel factors that regulate signaling at the neuromuscular junction, and 5) develop novel genetic methods / tools.

    • B.S. – Muhlenberg College
    • Ph.D. – Yale University
    • Postdoctoral – Yale University
    • Postdoctoral – University of Pennsylvania Perelman School of Medicine
       

    Fig 1: Ciliated sensory neuronsIdentifying biogenesis and cargo sorting mechanisms for extracellular vesicle subpopulations Extracellular vesicles (EVs) are membrane-wrapped structures that transfer bioactive macromolecules between cells and play key roles in development and homeostasis as well as the progression of pathological conditions including neurodegenerative diseases and cancer. Remarkably, a single cell can release multiple distinct EV subpopulations, each with different cargo enrichment. C. elegans CLHM-1 is expressed in the IL2, CEM, HOB and RnB sensory neurons and localizes to the cilia from which EVs are released (Fig. 1). We discovered that animals expressing functional GFP-tagged CLHM-1 at endogenous levels release CLHM-1::GFP in ciliary derived EVs. Fig 2: CLHM-1Analysis of animals expressing both tdTomato-tagged CLHM-1 and GFP-tagged PKD-2, a known cargo in EVs released from the same ciliated sensory neurons, showed that the two fluorescent proteins do not colocalize in EVs (Fig. 2). Our goal is to use strengths of the C. elegans system to define EV biogenesis mechanisms and understand how EV cargo sorting specificity is achieved.  

    Identification of CALHM channel regulators We are also utilizing the powerful C. elegans model to gain critical insights into cellular CALHM channel function. Our goal is to identify and characterize CLHM-1 regulators in order to determine the molecular mechanisms that control channel localization and function. We have isolated CLHM-1 regulators in C. elegans by performing an unbiased forward genetic screen for suppressors of toxicity associated with CLHM-1 over-expression. After identifying the causative mutations by a whole genome sequencing strategy, we will characterize the mutants using genetic, behavioral and cell biological approaches.

    Impact of Diet on Amyloid-beta Toxicity in C. elegans We use a C. elegans model of Alzheimer’s disease (AD) to identify factors that impact Aβ toxicity, a causative factor in AD pathogenesis. Expression of human Aβ1-42 in C. elegans causes fully penetrant, age-dependent paralysis. We found that loss of CLHM-1 had no effect on Aβ toxicity, however, while conducting these experiments we discovered that the type of E. coli diet that Aβ-expressing animals consume alters paralysis rate. Our goal is to determine how diet affects Aβ levels, mitochondrial morphology, mitochondrial function, and gene expression in Aβ-expressing C. elegans.

    Characterization of novel regulators of post-synaptic signaling at the NMJ C. elegans body-wall muscles are comparable to vertebrate skeletal muscles and provide an excellent model to study neuromuscular transmission. To identify novel factors that regulate post-synaptic cholinergic signaling we carried out a genome wide RNAi screen in C. elegans for gene knockdowns that cause hypersensitivity or resistance to the AChR agonist levamisole. We discovered 156 gene knockdowns that caused altered levamisole response. Our goal is to define the mechanism(s) by which neuromuscular transmission is altered by determining how the gene knockdowns affect locomotion, signaling, and synaptic structure using biomechanical, optogenetic and imaging approaches. 

    Fig 3: Schematic of a superselective primerA rapid, super-selective method for detection of single nucleotide variants With wide spread use of single nucleotide variants generated through mutagenesis screens, the million mutation project, and genome editing technologies there is pressing need for an efficient and low-cost strategy to detect single nucleotide variants. We developed a rapid and inexpensive method for detection of single nucleotide variants by adapting superselective primers for end-point PCR. Each superselective primer contains an anchor, bridge, and foot with the last nucleotide in the foot region determining specificity for the mutant allele versus wild type (Fig. 3). We explored how length, stability and sequence composition of each segment affected primer selectivity and developed simple rules for primer design (manuscript in preparation). We have demonstrated the utility of superselective primers for routine genotyping, detection of genome editing events, and colony PCR to identify successful site-directed mutagenesis constructs. Additional ongoing projects in the lab are aimed at developing novel genetics methods.

 

 

Jessica Tanis, Ph.D. <p>Assistant Professor </p>(302) 831-8439 jtanis@udel.edu 233 Wolf Hall <ul> <li>B.S. – Muhlenberg College </li><li>Ph.D. – Yale University </li><li>Postdoctoral – Yale University </li><li>Postdoctoral – University of Pennsylvania Perelman School of Medicine<br>  </li></ul><p>Calcium homeostasis modulator 1 (CALHM1) is an ion channel expressed in the brain and taste buds that plays important roles in cultured cortical neuron excitability and taste perception. Human genetic studies suggest that the P86L polymorphism in CALHM1 accelerates late onset Alzheimer’s disease onset, however, the physiological significance of CALHM1 activation in the mammalian brain remains unclear. CALHM1 and its <em>C. elegans</em> homolog, CLHM-1, exhibit similar biophysical properties when expressed in <em>Xenopus</em> oocytes and functional conservation when expressed in <em>C. elegans</em>. We are utilizing the anatomical simplicity, genetic tools, and easily quantifiable behaviors of <em>C. elegans</em> to define CLHM-1 function.</p><p><strong>Our study of <em>C. elegans</em> CLHM-1 has resulted in the development of diverse projects</strong>. Using a combination of genetic, imaging, behavioral, electrophysiological, and biochemical approaches members of my lab are seeking to 1) understand mechanisms underlying extracellular vesicle formation and cargo sorting, 2) identify regulators of CLHM-1 function, 3) understand the role of diet in amyloid-beta toxicity, 4) characterize novel factors that regulate signaling at the neuromuscular junction, and 5) develop novel genetic methods / tools.<br></p><p><strong><img src="/content-sub-site/PublishingImages/people/jtanis/fig1.png" alt="Fig 1: Ciliated sensory neurons" class="ms-rtePosition-2" style="margin:5px;" />Identifying biogenesis and cargo sorting mechanisms for extracellular vesicle subpopulations</strong> Extracellular vesicles (EVs) are membrane-wrapped structures that transfer bioactive macromolecules between cells and play key roles in development and homeostasis as well as the progression of pathological conditions including neurodegenerative diseases and cancer. Remarkably, a single cell can release multiple distinct EV subpopulations, each with different cargo enrichment. <em>C. elegans</em> CLHM-1 is expressed in the IL2, CEM, HOB and RnB sensory neurons and localizes to the cilia from which EVs are released (Fig. 1). We discovered that animals expressing functional GFP-tagged CLHM-1 at endogenous levels release CLHM-1::GFP in ciliary derived EVs. <img src="/content-sub-site/PublishingImages/people/jtanis/fig2.png" class="ms-rtePosition-2" alt="Fig 2: CLHM-1" style="margin:5px;" />Analysis of animals expressing both tdTomato-tagged CLHM-1 and GFP-tagged PKD-2, a known cargo in EVs released from the same ciliated sensory neurons, showed that the two fluorescent proteins do not colocalize in EVs (Fig. 2). Our goal is to use strengths of the <em>C. elegans</em> system to define EV biogenesis mechanisms and understand how EV cargo sorting specificity is achieved.  </p><p><strong>Identification of CALHM channel regulators</strong> We are also utilizing the powerful <em>C. elegans</em> model to gain critical insights into cellular CALHM channel function. Our goal is to identify and characterize CLHM-1 regulators in order to determine the molecular mechanisms that control channel localization and function. We have isolated CLHM-1 regulators in <em>C. elegans</em> by performing an unbiased forward genetic screen for suppressors of toxicity associated with CLHM-1 over-expression. After identifying the causative mutations by a whole genome sequencing strategy, we will characterize the mutants using genetic, behavioral and cell biological approaches.</p><p><strong>Impact of Diet on Amyloid-beta Toxicity in <em>C. elegans</em></strong> We use a <em>C. elegans</em> model of Alzheimer’s disease (AD) to identify factors that impact Aβ toxicity, a causative factor in AD pathogenesis. Expression of human Aβ1-42 in <em>C. elegans</em> causes fully penetrant, age-dependent paralysis. We found that loss of CLHM-1 had no effect on Aβ toxicity, however, while conducting these experiments we discovered that the type of <em>E. coli</em> diet that Aβ-expressing animals consume alters paralysis rate. Our goal is to determine how diet affects Aβ levels, mitochondrial morphology, mitochondrial function, and gene expression in Aβ-expressing <em>C. elegans</em>.</p><p><strong>Characterization of novel regulators of post-synaptic signaling at the NMJ</strong> <em>C. elegans</em> body-wall muscles are comparable to vertebrate skeletal muscles and provide an excellent model to study neuromuscular transmission. To identify novel factors that regulate post-synaptic cholinergic signaling we carried out a genome wide RNAi screen in <em>C. elegans</em> for gene knockdowns that cause hypersensitivity or resistance to the AChR agonist levamisole. We discovered 156 gene knockdowns that caused altered levamisole response. Our goal is to define the mechanism(s) by which neuromuscular transmission is altered by determining how the gene knockdowns affect locomotion, signaling, and synaptic structure using biomechanical, optogenetic and imaging approaches. </p><p> <strong><img src="/content-sub-site/PublishingImages/people/jtanis/fig3.png" class="ms-rtePosition-2" alt="Fig 3: Schematic of a superselective primer" style="margin:5px;" />A rapid, super-selective method for detection of single nucleotide variants</strong> With wide spread use of single nucleotide variants generated through mutagenesis screens, the million mutation project, and genome editing technologies there is pressing need for an efficient and low-cost strategy to detect single nucleotide variants. We developed a rapid and inexpensive method for detection of single nucleotide variants by adapting superselective primers for end-point PCR. Each superselective primer contains an anchor, bridge, and foot with the last nucleotide in the foot region determining specificity for the mutant allele versus wild type (Fig. 3). We explored how length, stability and sequence composition of each segment affected primer selectivity and developed simple rules for primer design (manuscript in preparation). We have demonstrated the utility of superselective primers for routine genotyping, detection of genome editing events, and colony PCR to identify successful site-directed mutagenesis constructs. Additional ongoing projects in the lab are aimed at developing novel genetics methods.<br></p><p><strong><img src="/content-sub-site/PublishingImages/people/jtanis/tanislab-group.png" alt="Tanis Lab" class="ms-rtePosition-2" style="margin:5px;" />Denis Touroutine </strong>Postdoc (MS Chemistry, Moscow State University; PhD, University of Illinois - Chicago, laboratory of Janet Richmond) EV biogenesis and cargo sorting; CLHM-1 regulators; novel methods development</p><p><strong>Michael Clupper</strong> Graduate Student (BS, Penn State University) EV biogenesis and cargo sorting</p><p><strong>Andy Lam</strong> Graduate Student (BA, University of Delaware) Impact of diet on amyloid-beta toxicity; NMJ signaling</p><p><strong>Rachael Gill</strong> Graduate Student (BS, Liberty University) EV biogenesis and cargo sorting</p><p><strong>Jaclyn Littmann</strong> Undergraduate BS Biological Sciences major (University of Delaware) EV biogenesis and cargo sorting</p><p><strong>Charlotte Leslie</strong> Undergraduate BS Biological Sciences major (University of Delaware) Impact of diet on amyloid-beta toxicity</p><p><strong>Erin Smith</strong> Undergraduate BS Biological Sciences major (University of Delaware) NMJ signaling</p><p><strong>Elizabeth Whelahan</strong> Undergraduate BA Exercise Science major (University of Delaware) NMJ signaling</p><p><strong>Previous Group Members</strong></p><p><strong>Kirsten Kervin</strong> Graduate Student (BS Delaware State University, MS University of Delaware) Impact of diet on amyloid-beta toxicity; NMJ signaling. Current - Laboratory Technician II at WuXi AppTec.</p><p><strong>Elaine Miller</strong> Research Associate (BS, University of California – Davis) CLHM-1 regulators; NMJ signaling. Current – graduate student at George Washington University.</p><p><strong>Shrey Patel</strong> Undergraduate Biological Sciences Major (BA, University of Delaware) NMJ signaling. Current – medical student at Drexel University College of Medicine.<br></p><ul><li>   Ma Z, Taruno A, Ohmoto M, Jyotaki M, Lim JC, Miyazaki H, Niisato N, Marunaka Y, Lee RJ, Hoff H, Payne R, Demuro A, Parker I, Mitchell CH, Henao-Mejia J, <strong>Tanis JE</strong>, Matsumoto I, Tordoff MG, Foskett JK. (2018)<a href="https://www.ncbi.nlm.nih.gov/pubmed/29681531"> CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes</a>. Neuron 98(3):547-561.e10. doi: 10.1016/j.neuron.2018.03.043. Epub 2018 Apr 19.</li><li> <strong>Tanis JE</strong>, Ma Z, Foskett JK. (2017) <a href="https://www.ncbi.nlm.nih.gov/pubmed/28515089">The NH2 terminus regulates voltage-dependent gating of CALHM ion channels</a>. Am J Physiol Cell Physiol 313(2):C173-C186.</li><li> Collins KM, Bode A, Fernandez RW, <strong>Tanis JE</strong>, Brewer JC, Creamer MS, Koelle MR. (2016) <a href="https://www.ncbi.nlm.nih.gov/pubmed/27849154">Activity of the <em>C. elegans</em> egg-laying behavior circuit is controlled by competing activation and feedback inhibition</a>. Elife e21126.</li><li> Vais H, Mallilankaraman K, Mak DD, Hoff H, Payne R, <strong>Tanis JE</strong>, Foskett JK. (2016) <a href="http://www.ncbi.nlm.nih.gov/pubmed/26774479">EMRE Is a Matrix Ca2+ Sensor that Governs Gatekeeping of the Mitochondrial Ca2+ Uniporter</a>. Cell Rep. 14(3):403-10.</li><li> Ma Z, <strong>Tanis JE</strong>, Taruno A, Foskett JK. (2015) <a href="http://www.ncbi.nlm.nih.gov/pubmed/26603282">Calcium homeostasis modulator (CALHM) ion channels</a>. Pflugers Arch. 468(3):395-403.</li><li> Vais H, <strong>Tanis JE</strong>, Müller M, Payne R, Mallilankaraman K, Foskett JK. (2015) <a href="http://www.ncbi.nlm.nih.gov/pubmed/26445506">MCUR1, CCDC90A, Is a Regulator of the Mitochondrial Calcium Uniporter</a>. Cell Metab. 22(4):533-5.</li><li> Vingtdeux V, <strong>Tanis JE</strong>, Chandakkar P, Zhao H, Dreses-Werringloer U, Campagne F, Foskett JK, Marambaud P. (2014) <a href="http://www.ncbi.nlm.nih.gov/pubmed/25386646">Effect of the CALHM1 G330D and R154H human variants on the control of cytosolic Ca2+ and Aβ levels</a>. PLoS One. 9(11):e112484.</li><li> Krajacic P*, Pistilli EE*, <strong>Tanis JE*</strong>, Khurana TS, Lamitina ST. (2013) <a href="http://www.ncbi.nlm.nih.gov/pubmed/24244862">FER-1/Dysferlin promotes cholinergic signaling at the neuromuscular junction in <em>C. elegans</em> and mice</a>. Biol. Open 2(11):1245-52.</li><li> <strong>Tanis JE</strong>, Ma Z, Krajacic P, He L, Foskett JK, Lamitina T. (2013) <a href="http://www.ncbi.nlm.nih.gov/pubmed/23884934">CLHM-1 is a functionally conserved and conditionally toxic Ca2+-permeable ion channel in Caenorhabditis elegans</a>. J. Neurosci. 33(30):12275-86.</li><li> Somasekharan S, <strong>Tanis J</strong>, Forbush B. (2012) <a href="http://www.ncbi.nlm.nih.gov/pubmed/22437837">Loop diuretic and ion-binding residues revealed by scanning mutagenesis of transmembrane helix 3 (TM3) of Na-K-Cl cotransporter (NKCC1)</a>. J. Biol. Chem. 287(21):17308-17.</li><li> <strong>Tanis JE</strong>, Bellemer A, Moresco JJ, Forbush B, Koelle MR. (2009) <a href="http://www.ncbi.nlm.nih.gov/pubmed/19675228">The potassium chloride cotransporter KCC-2 coordinates development of inhibitory neurotransmission and synapse structure in Caenorhabditis elegans</a>. J. Neurosci. 29(32):9943-54.</li><li> Rinehart J, Maksimova YD, <strong>Tanis JE</strong>, Stone KL, Hodson CA, Zhang J, Risinger M, Pan W, Wu D, Colangelo CM, Forbush B, Joiner CH, Gulcicek EE, Gallagher PG, Lifton RP. (2009) <a href="http://www.ncbi.nlm.nih.gov/pubmed/19665974">Sites of regulated phosphorylation that control K-Cl cotransporter activity</a>. Cell 138(3):525-36.</li><li> <strong>Tanis JE</strong>, Moresco JJ, Lindquist RA, Koelle MR. (2008) <a href="http://www.ncbi.nlm.nih.gov/pubmed/18202365">Regulation of serotonin biosynthesis by the G proteins Galphao and Galphaq controls serotonin signaling in Caenorhabditis elegans</a>. Genetics 178(1):157-69.<br></li></ul><img alt="" src="/Images%20Bios/Tanis_Jessica.jpg" style="BORDER:0px solid;" />

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  • Department of Biological Sciences
  • 105 The Grn, Room 118 Wolf Hall
  • Newark, DE 19716, USA
  • University of Delaware
  • Phone: 302-831-6977
  • bio-questions@udel.edu