B.S., Wofford College, Chemistry, 2002
Ph.D., University of South Carolina, Biochemistry, 2007
August 2014 – present: Assistant Professor, Department of Biochemistry, Virginia Polytechnic
Institute and State University, Blacksburg VA
July 2011- August 2014: Research Associate, Department of Chemistry, The Scripps Research
Institute, Jupiter FL
July 2009 – July 2011: NIH Ruth L. Kirschstein Postdoctoral Fellow, Harvard Medical School and
Massachusetts General Hospital, Department of Microbiology and Molecular Genetics/Division of
Infectious Diseases, Boston MA
Selected Major Awards
2009-2011 NIH Ruth L. Kirschstein Postdoctoral Fellow, Harvard Medical School and Massachusetts
General Hospital, Department of Microbiology and Molecular Genetics/Division of Infectious
Diseases, Boston MA
2008-2009 NIH T32 Postdoctoral Training Grant, Harvard Medical School, Department of Microbiology
and Molecular Genetics, Boston MA
More than 15% of carcinomas can be attributed to known infectious agents such as bacteria and viruses. Fusobacterium nucleatum is a gram‐negative bacterium that is significantly overrepresented in the colonic tissue of patients with colorectal cancer. We will be working at the interface of chemistry and biology to determine the role of the microbiome in cancer using: chemical biology, x‐ray crystallography, biochemistry, molecular genetics, enzymology, and cell biology.
1) Uncovering The Role of Autotransporters In Inflammation And Cancer
Autotransporters are type V secreted proteins that can be present on the surface of bacteria, or secreted after being cleaved from the outer membrane. They are the largest family of bacteria virulence factors, and most have been characterized as adhesins and proteases. Previous studies have shown these proteins to be responsible for invoking an inflammatory response during infection. We will investigate if autotransporter adhesins and proteases could be triggering this inflammation in cancer.
2) Developing Inhibitors And Chemical Probes That Target The Protease Family Of Autotransporters
Serine and cysteine protease autotransporters are key tools that gram‐negative bacteria use for survial and infection. We will take a chemical biology approach to develop inhibitors and probes to determine if inhibiting these proteins leads to altered epithelial invasion, and if this in turn leads to a decreased prevalance of Fusobacterium being associated with the progression of colorectal cancer. Simple scaffolds will be used to develop diverse libraries that can be screened and fine tuned for specific proteins within the family.
3) Uncovering F. nucleatum Proteins That Are Upregulated During Infection In Colorectal Cancer
Bacteria upregulate numerous genes during infection, and these gene patterns can be specific for the tissue that is infected. While it is known which human genes are upregulated during infection with Fusobacterium, which genes are upregulated in the bacterium have not been studied. We will use RNA‐SEQ technology to determine the gene expression patterns during infection of cultured human colonocytes, as well as mouse models of infection. This data will provide us with a list of genes that are crucial for bacterial invasion, which may lead us to discover specific pathways that produce proteins or metabolites that illicit an inflammatory response.
Lewis HD, Liddle J, Coote JE, Atkinson SJ, Barker MD, Bax BD, Bicker KL, Bingham RP, Campbell M, Chen YH, Chung CW, Craggs PD, Davis RP, Eberhard D, Joberty G, Lind KE, Locke K, Maller C, Martinod K, Patten C, Polyakova O, Rise CE, Rüdiger M, Sheppard RJ, Slade DJ, Thomas P, Thorpe J, Yao G, Drewes G, Wagner DD, Thompson PR, Prinjha RK, Wilson DM. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nat Chem Biol. 2015 Mar;11(3):189-91. doi: 10.1038/nchembio.1735. Epub 2015 Jan 26. PubMed PMID: 25622091.
Slade DJ, Fang P, Dreyton CJ, Zhang Y, Fuhrmann J, Rempel D, Bax BD, Coonrod SA, Lewis HD, Guo M, Gross ML, Thompson PR. Protein Arginine Deiminase 2 Binds Calcium in an Ordered Fashion: Implications for Inhibitor Design. ACS Chem Biol. 2015 Jan 26. [Epub ahead of print] PubMed PMID: 25621824.
Slade DJ, Horibata S, Coonrod SA, Thompson PR. A novel role for protein arginine deiminase 4 in pluripotency: the emerging role of citrullinated histone H1 in cellular programming. Bioessays. 2014 Aug;36(8):736-40. doi: 10.1002/bies.201400057. Epub 2014 May 30. PubMed PMID: 24889365; PubMed Central PMCID: PMC4151298.
Slade DJ, Subramanian V, Thompson PR. Pluripotency: citrullination unravels stem cells. Nat Chem Biol. 2014 May;10(5):327-8. doi: 10.1038/nchembio.1504. PubMed PMID: 24743255.
Slade DJ, Subramanian V, Fuhrmann J, Thompson PR. Chemical and biological methods to detect post-translational modifications of arginine. Biopolymers. 2014 Feb;101(2):133-43. doi: 10.1002/bip.22256. PubMed PMID: 23576281; PubMed Central PMCID: PMC3900596.
Rohrbach AS, Slade DJ, Thompson PR, Mowen KA. Activation of PAD4 in NET formation. Front Immunol. 2012 Nov 29;3:360. doi: 10.3389/fimmu.2012.00360. eCollection 2012. PubMed PMID: 23264775; PubMed Central PMCID: PMC3525017.
Zhang X, Bolt M, Guertin MJ, Chen W, Zhang S, Cherrington BD, Slade DJ, Dreyton CJ, Subramanian V, Bicker KL, Thompson PR, Mancini MA, Lis JT, Coonrod SA. Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor α target gene activation. Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):13331-6. doi: 10.1073/pnas.1203280109. Epub 2012 Aug 1. PubMed PMID: 22853951; PubMed Central PMCID: PMC3421185.
Fixen KR, Janakiraman A, Garrity S, Slade DJ, Gray AN, Karahan N, Hochschild A, Goldberg MB. Genetic reporter system for positioning of proteins at the bacterial pole. MBio. 2012 Feb 28;3(2). pii: e00251-11. doi: 10.1128/mBio.00251-11. Print 2012. PubMed PMID: 22375072; PubMed Central PMCID: PMC3302567.
Slade DJ, Lovelace LL, Chruszcz M, Minor W, Lebioda L, Sodetz JM. Crystal structure of the MACPF domain of human complement protein C8 alpha in complex with the C8 gamma subunit. J Mol Biol. 2008 May 30;379(2):331-42. doi: 10.1016/j.jmb.2008.03.061. Epub 2008 Apr 3. PubMed PMID: 18440555; PubMed Central PMCID: PMC2443722.
Lovelace LL, Chiswell B, Slade DJ, Sodetz JM, Lebioda L. Crystal structure of complement protein C8gamma in complex with a peptide containing the C8gamma binding site on C8alpha: implications for C8gamma ligand binding. Mol Immunol. 2008 Feb;45(3):750-6. Epub 2007 Aug 9. PubMed PMID: 17692377.
Chiswell B, Slade DJ, Sodetz JM. Binding of the lipocalin C8gamma to human complement protein C8alpha is mediated by loops located at the entrance to the C8gamma ligand binding site. Biochim Biophys Acta. 2006 Sep;1764(9):1518-24. Epub 2006 Jul 28. PubMed PMID: 16935577.
Slade DJ, Chiswell B, Sodetz JM. Functional studies of the MACPF domain of human complement protein C8alpha reveal sites for simultaneous binding of C8beta, C8gamma, and C9. Biochemistry. 2006 Apr 25;45(16):5290-6. PubMed PMID: 16618117.