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Joshua Clair Snyder, PhD

Assistant Professor of Surgery
Assistant Research Professor of Cell Biology
Office: Msrbi Rm 475A, Durham, NC 27710
Campus Mail: DUMC Box 3287 Med Ctr, Durham, NC 27710

My research objective is to translate basic science discoveries into treatments and cures for cancer. My work primarily focuses on G protein-coupled receptors (GPCR)s as a primary target in cancer. GPCRs are the largest family of receptors encoded by the genome, tightly control cell signaling, and regulate physiology in a diversity of tissues. As such, they are historically among the best targets for small molecule therapy in the clinic. The leucine-rich G protein-coupled receptor-5 (Lgr5) is particularly interesting since it is expressed in stem and cancer stem cells in a myriad of tissues. However, the function of Lgr5 is still largely unknown. Currently, my work utilizes cutting-edge multidisciplinary approaches to tackle this important challenge. This includes genetic engineering of fluorescently labelled mice, high-content confocal microscopy and cell behavior modeling, organoid culturing and genome editing, and fluorescent based approaches for high-throughput screening of receptor trafficking.

 

Using these approaches, we have made several important discoveries regarding Lgr5 that are facilitating future studies. We found that Lgr5 drives the formation of very long cellular protrusions that serve as scaffolds for cell signaling. We are continuing to investigate the mechanistic importance of this finding using mouse models and intestinal organoid cultures to view this process in living mice. Another key observation was our discovery that Lgr5 internalization and trafficking are critical for regulating its function. Current work is now working toward a more mechanistic characterization of Lgr5 trafficking using fluorescent sensors that are capable of quantitatively assessing this dynamic process. We are also actively screening small molecule libraries in an effort to discover potential agonists/antagonists of Lgr5 that may be useful clinically in cancer treatment or in tissue regeneration. Lastly, we are continuing to develop additional technologies for directing gene expression in vivo in order to study the structure/function of tumor driver genes with greater sensitivity and more cellular resolution. Our strategy enables the simultaneous expression of multiple driver genes in vivo along with the ability to monitor their effects on cell fate and behavior. Importantly, many of the tools that we have developed are broadly applicable to other receptors and candidate tumor driver genes for which we are open for collaboration.

 

 

Education and Training

  • Ph.D., University of Pittsburgh School of Medicine, 2009

Publications

Snyder, JC, Rochelle, LK, Ray, C, Pack, TF, Bock, CB, Lubkov, V, Lyerly, HK, Waggoner, AS, Barak, LS, and Caron, MG. "Inhibiting clathrin-mediated endocytosis of the leucine-rich G protein-coupled receptor-5 diminishes cell fitness." The Journal of biological chemistry 292, no. 17 (April 2017): 7208-7222.

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Urs, NM, Gee, SM, Pack, TF, McCorvy, JD, Evron, T, Snyder, JC, Yang, X, Rodriguiz, RM, Borrelli, E, Wetsel, WC, Jin, J, Roth, BL, O'Donnell, P, and Caron, MG. "Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties." Proceedings of the National Academy of Sciences of the United States of America 113, no. 50 (December 2016): E8178-E8186.

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Jean-Charles, P-Y, Snyder, JC, and Shenoy, SK. "Chapter One - Ubiquitination and Deubiquitination of G Protein-Coupled Receptors." Progress in molecular biology and translational science 141 (January 2016): 1-55. (Review)

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Snyder, JC, Pack, TF, Rochelle, LK, Chakraborty, SK, Zhang, M, Eaton, AW, Bai, Y, Ernst, LA, Barak, LS, Waggoner, AS, and Caron, MG. "A rapid and affordable screening platform for membrane protein trafficking." BMC biology 13 (December 17, 2015): 107-.

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Snyder, JC, Rochelle, LK, Marion, S, Lyerly, HK, Barak, LS, and Caron, MG. "Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions." Journal of cell science 128, no. 6 (March 2015): 1230-1240.

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Snyder, JC, Mackaness, CA, Sopher, MR, Huber, JP, Disantis, EJ, Senecal, AJ, Vaughn, BP, Desantis, RS, Tobelmann, PE, Balauff, NMH, Barry, PM, Show, MD, Speering, LH, Genareo, CA, Brenner, FJ, and Ray, DB. "The complete mitochondrial genome sequence of the Canada goose (Branta canadensis)." Mitochondrial DNA 26, no. 5 (January 2015): 672-673.

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Snyder, JC, Rochelle, LK, Barak, LS, and Caron, MG. "Correction: The Stem Cell-Expressed Receptor Lgr5 Possesses Canonical and Functionally Active Molecular Determinants Critical to β-arrestin-2 Recruitment." PloS one 9, no. 1 (2014).

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Caron, MG, Urs, NM, Snyder, JC, and Peterson, SM. "Integrated Approaches to Understand the Actions of GPCRs: The b-Arrestin-Dependent D2R Mediated Signaling Through Akt/GSK3." (December 1, 2013): 99-100. (Chapter)

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Barak, LS, Bai, Y, Snyder, JC, Wang, J, Chen, W, and Caron, MG. "Triphenylmethane dye activation of beta-arrestin." Biochemistry 52, no. 32 (August 13, 2013): 5403-5414.

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Snyder, JC, Rochelle, LK, Lyerly, HK, Caron, MG, and Barak, LS. "Constitutive internalization of the leucine-rich G protein-coupled receptor-5 (LGR5) to the trans-Golgi network." J Biol Chem 288, no. 15 (April 12, 2013): 10286-10297.

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