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Joshua Clair Snyder, PhD

Assistant Professor of Surgery
Assistant 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.

We are currently accepting applications for a post doctoral research fellow that will work on projects related to Lgr5 drug discovery and the cell fitness mechanisms driving tumorigenesis. Qualified applicants can apply here: https://careers.nationalpostdoc.org/job/postdoctoral-fellow-cell-biology-and-pharmacologycancer-biology/40147366/.

 

Education and Training

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

Publications

Urs, Nikhil M., Joshua C. Snyder, Jacob P. R. Jacobsen, Sean M. Peterson, and Marc G. Caron. “Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action.” Proc Natl Acad Sci U S A 109, no. 50 (December 11, 2012): 20732–37. https://doi.org/10.1073/pnas.1215489109.

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Hashimoto, Shuichi, Huaiyong Chen, Jianwen Que, Brian L. Brockway, Jeffrey A. Drake, Joshua C. Snyder, Scott H. Randell, and Barry R. Stripp. “β-Catenin-SOX2 signaling regulates the fate of developing airway epithelium.” J Cell Sci 125, no. Pt 4 (February 15, 2012): 932–42. https://doi.org/10.1242/jcs.092734.

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Snyder, Joshua C., Susan D. Reynolds, John W. Hollingsworth, Zhuowei Li, Naftali Kaminski, and Barry R. Stripp. “Clara cells attenuate the inflammatory response through regulation of macrophage behavior.” Am J Respir Cell Mol Biol 42, no. 2 (February 2010): 161–71. https://doi.org/10.1165/rcmb.2008-0353OC.

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Giangreco, Adam, Esther N. Arwert, Ian R. Rosewell, Joshua Snyder, Fiona M. Watt, and Barry R. Stripp. “Stem cells are dispensable for lung homeostasis but restore airways after injury.” Proc Natl Acad Sci U S A 106, no. 23 (June 9, 2009): 9286–91. https://doi.org/10.1073/pnas.0900668106.

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Snyder, Joshua C., Anna C. Zemke, and Barry R. Stripp. “Reparative capacity of airway epithelium impacts deposition and remodeling of extracellular matrix.” Am J Respir Cell Mol Biol 40, no. 6 (June 2009): 633–42. https://doi.org/10.1165/rcmb.2008-0334OC.

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Zemke, Anna C., Joshua C. Snyder, Brian L. Brockway, Jeffrey A. Drake, Susan D. Reynolds, Naftali Kaminski, and Barry R. Stripp. “Molecular staging of epithelial maturation using secretory cell-specific genes as markers.” Am J Respir Cell Mol Biol 40, no. 3 (March 2009): 340–48. https://doi.org/10.1165/rcmb.2007-0380OC.

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Reynolds, Susan D., Paul R. Reynolds, Joshua C. Snyder, Fadra Whyte, Kevin J. Paavola, and Barry R. Stripp. “CCSP regulates cross talk between secretory cells and both ciliated cells and macrophages of the conducting airway.” Am J Physiol Lung Cell Mol Physiol 293, no. 1 (July 2007): L114–23. https://doi.org/10.1152/ajplung.00014.2007.

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Hussein, M. A., J. Kurtzburg, J. Snyder, C. Kozak, D. A. McLain, and R. Bukowski. “Peg-L-Asparaginase (PL-A) in advanced multiple myeloma (MM): A novel agent with therapeutic potential.” In Blood, 88:3607–3607. W B SAUNDERS CO, 1996.

Scholars@Duke

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