David Boone Adjunct Associate Professor

Biology of Human Intestinal Diseases
David Boone

Research Interests:

The Boone lab is interested in disorders that affect the gastrointestinal tract. Our major objectives are to understand the pathogenesis of inflammatory bowel diseases (IBD; Crohn’s Disease & Ulcerative Colitis), colon cancer and obesity. Current projects include:

The Microbiome in Intestinal Health

We have generated a new knockout mouse that has several interesting phenotypes including susceptibility to IBD and resistance to high fat diet-induced obesity. Overall our current model is that the gene we have knocked out encodes a protein important for maintaining a dynamic intestinal microbiome. We are investigating how the loss of this protein leads to an altered intestinal microbiome that affects health.


Intestinal Epithelial Control of Intestinal Inflammation

We have generated a transgenic mouse that has reduced NF-kB activity in intestinal epithelial cells. Surprisingly, these mice are far more prone to IBD driven by innate immune cells. Our model is that the reduced epithelial NF-kB activity alters the production of a subset of antimicrobial peptides (AMPs) allowing a subset of microbes to infiltrate the intestinal mucus layer and therefore drive colitis in a genetically susceptible host. We are currently investigating the nature of the microbes that infiltrate the mucus and the nature of the inflammation that they cause.


Autophagy and Colon Cancer

We have found that a genetic variant found in the human population at a frequency approaching 50% is protective in individuals who develop colorectal cancer (CRC), both in terms of long-term survival and the frequency of metastases. This variant affects the function of a core autophagy gene called ATG16L1. Using gene-targeted human cell lines we have shown that this variant increases the capacity of CRC cells to produce type I interferons. Our model is that the genetic variant in ATG16L1 results in type I interferon production by CRC cells and that this induces innate and adaptive immune cell killing of CRC tumors to promote patient survival and prevent metastases.

 

Biography:

  • Adjunct Associate Professor of Biology, University of Notre Dame 2014-Present
  • Associate Professor of Microbiology and Immunology, Indiana University School of Medicine – South Bend 2014-Present
  • Assistant Professor of Medicine, University of Chicago 2006-2013
  • Adjunct Assistant Professor, University of California, San Francisco 2004-2006
  • Postdoctoral fellow, University of Chicago 1997-2004
  • Ph.D., University of Ottawa 1997
  • B.Sc., University of Waterloo 1989

 

Recent Papers:

  • *EG Lee, *DL Boone, S Chai, SL Libby, M Chien, JP Lodolce, A Ma (2000). Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 289:2350-2354.
  • PR Burkett, RM Koka, JP Lodolce, MC Chien, F Chan and A Ma and DL Boone. (2003).  IL-15Ra expression on CD8 T cells is dispensable for T cell memory.  Proceedings of the National Academy of Sciences USA. 100:4724-4729.
  • IE Wertz, KM O'Rourke, H Zhou, M Eby, L Aravind, S Seshagiri, P Wu, C Wiesmann, R Baker, DL Boone, A Ma, EV Koonin and VM Dixit. (2004) De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signaling. Nature. 430:694-699.
  • *DL Boone, *EE Turer, EG Lee, RC Ahmad, MT Wheeler, C Tsui, P Hurley, M Chien, S Chai, O Hitotsumatsu, E McNally, C Pickart, and A Ma (2004). The ubiquitin modifying enzyme A20 is required for terminating Toll-like receptor responses. Nature Immunology. 5:1052-1050.
  • N Netzer, JM Goodenbour, A David, KA Dittmar, RB Jones, JR Schneider, D Boone, EM Eves, MR Rosner, JS Gibbs, A Embry, B Dolan, S Das, H Hickman, P Berglund, JR Bennink, JW Yewdell and T Pan (2009). Innate immune and chemically triggered oxidative stress modifies translational fidelity. Nature Nov 26; 462(7272): 522-6.
  • Lodolce JP, Kolodziej LK, Rhee L, Kariuki SN, Franek BS, McGreal NM, Logsdon MF, Bartulis SJ, Perera MA, Ellis NA, Adams EJ, Hanauer SB, Jolly M, Niewold TB, and Boone DL (2010). African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity. Journal of Immunology. 2010 Jun 15; 184(12): 7001-9
  • Lauren E. Kolodziej, James P. Lodolce, Jonathan E. Chang, Jeffrey R. Schneider, Wesley A. Grimm, Sarah J. Bartulis, Xiaorong Zhu, Jeannette S. Messer, Stephen F. Murphy, Nishith Reddy, Jerrold R. Turner, David L. Boone (2011) TNFAIP3 Maintains Intestinal Barrier Function and Supports Epithelial Cell Tight Junctions. PLoS One 6(10)
  • L Rhee, SF Murphy, LE Kolodziej, WA Grimm, CR Weber, JP Lodolce, JE Chang, SJ Bartulis, JS Messer, JR Schneider, S Paski, TM Nero, DL Boone (2012) Expression Of TNFAIP3 In Intestinal Epithelial Cells Protects From DSS But Not TNBS-Induced Colitis. American Journal of Physiology – Gastroenterology. Jul 15; 303(2): G220-7.
  • JS Messer, SF Murphy, MF Logsdon, SJ Bartulis, JP Lodolce, DL Boone (2013) The Crohn’s Disease Associated ATG16L1 variant and Salmonella Invasion. BMJ Open Jun 20;3(6)
  • Murphy SF, Rhee L, Grimm WA, Weber CR, Messer JS, Lodolce JP, Chang JE, Bartulis SJ, Nero T, Kukla RA, MacDougall G, Binghay C, Kolodziej LE and Boone DL (2014) Intestinal Epithelial Expression of TNFAIP3 Results in Microbial Invasion of the Inner Mucus Layer and Induces Colitis in IL-10-Deficient Mice. American Journal of Physiology – Gastroenterology. Nov 1;307(9):G871-82.
  • Wesley A Grimm, Jeannette S Messer, Stephen F Murphy, Thomas Nero, James P Lodolce, Christopher R Weber, Mark F Logsdon, Sarah Bartulis, Brooke E Sylvester, Amanda Springer, Urszula Dougherty, Timothy B Niewold, Sonia S Kupfer, Nathan Ellis, Dezheng Huo, Marc Bissonnette, David L Boone (2014) The Thr300Ala variant in ATG16L1 is associated with improved survival in human colorectal cancer and enhanced production of type I interferon. Gut. in press.