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Derek Abbott, M.D., Ph.D.Assistant ProfessorMailing Address: fax: (216) 368-0494 email: Derek.Abbott@Case.edu |
Biography
Derek Abbott graduated from the University of Virginia in 1993. He then matriculated to Vanderbilt
University School of Medicine as an MSTP Student. While a graduate student, he studied the breast cancer
genes BRCA1 and BRCA2, ultimately attaining a Ph.D. in Cell Biology. After the completion of his
medical school requirements, Dr. Abbott continued his clinical training in Anatomic Pathology at Brigham
and Women's Hospital in Boston, MA. After completing his residency, Dr. Abbott joined the lab of Dr.
Lewis Cantley in the Department of Systems Biology at Harvard Medical School. While in Lew Cantley's lab,
Dr. Abbott began deciphering the signal transduction cascade initiated bacterial activation of the
Crohn's Disease susceptibility gene NOD2. This work ultimately led to the attainment of a Burroughs
Wellcome Career Award in 2006. Dr. Abbott joined Case Western Reserve University's Department of Pathology
in the fall of 2006.
Research
As humans, we are constantly exposed to disease-causing bacteria, fungi and viruses. Whether it is from
a cough on a crowded airplane, a handshake from a business partner or the ingestion of undercooked
chicken, our bodies are in a constant battle to recognize and combat bacteria and viruses. Not only do we
have to activate our immune system to clear our bodies of these pathogens, we also have to deactivate
our immune system after this initial activation. An overactive immune system can damage the body, leading
to such autoimmune diseases as Rheumatoid Arthritis, Multiple Sclerosis and Crohn's Disease. Crohn's
Disease is a devastating disease characterized by bloody diarrhea, severe abdominal pain and by an
overall decrease in life-expectancy of approximately 15 years. Crohn's Disease arises from an
inappropriate immune response to the bacteria normally present in the intestine. Normally, the
intestine distinguishes normal from pathogenic bacteria, activating the immune system to eradicate
pathogenic bacteria. After this eradication, the immune system must then be deactivated to
prevent self-damage. In Crohn's Disease, the intestine responds inappropriately to the pathogenic
bacteria. The initial immune response is too active, and the subsequent deactivation of this immune
response is inadequate. The end result is an inflamed intestine producing severe pain and bloody
diarrhea. While the intestinal bacteria play a role in the pathogenesis of Crohn's Disease, the
patient's intestine also plays a role. The Crohn's Disease - susceptibility gene, NOD2, is an
intestinal protein that is activated by these intestinal bacteria. Upon activation by these
intestinal bacteria, NOD2 causes the release of a number of inflammatory mediators (cytokines) that help
to establish an appropriate immune response. A large number of Crohn's Disease patients have a non-
functional version of NOD2, and the activation of this faulty protein leads to an inability to tailor
the intestinal immune response to bacteria. The end result is a viscous cycle of inflammation,
ultimately resulting in Crohn's Disease. Our work centers both on the mechanism of activation of NOD2 and
on the mechanism of cytokine release by NOD2. We are attempting to dissect the signaling pathways
responsible for NOD2-induced Crohn's Disease, and we hope that this work leads to the identification of
novel drug targets such that Crohn's Disease can be more effectively treated.
Publications
Abbott, D.W., Wilkins, A., Asara, J.M., and L.C. Cantley. (2004). "The Crohn's Disease gene, NOD2, induces
the ubiquitinylation of NEMO at a novel site." Current Biology, 14: 2217-2227. ("News and Views"
discussing paper, Current Biology, 14: R1040-R1042.; Faculty of 100 citation: "Must Read"; paper selected
in Research Highlights at both Nature Immunology and Nature Reviews Immunology, Feb. 2005)
Kang, C., Abbott, D.W., Cantley, L.C. and R. Husson. (2005) "The Mycobacterium tuberculosis serine/ threonine kinases PknA and PknB: substrate identification and regulation of cell shape" Genes and Development 19:1692-1704.
Abbott, D.W. and D.B. Polk. (2005) "NODing off and ramping up." Inflammatory Bowel Diseases 11:860-861.
Abbott, D.W., Yang, Y., Hutti, J.E., Madhavarapu, S., Kelliher, M.A. and L.C. Cantley. (2007) "Coordinated regulation of toll-like receptor and NOD2 signaling through K63-linked polyubiquitin chains." Molecular and Cellular Biology 27:6012-6025.
Hutti, J.E., Turk, B.E., Asara, J.M., Ma, A., Cantley, L.C. And D.W. Abbott. (2007) "IkappaB kinase beta phosphorylates the K63 deubiquitinase A20 to cause feedback inhibition of the NF-kappaB pathway." Molecular and Cellular Biology. 27(21):7451-61.
Clark, N.M., Marinis, J.M, Cobb, B.A and D.W. Abbott. (2008) "MEKK4 sequesters RIP2 to dictate NOD2 signal specificity." Current Biology. 18:1402-8.
Tao, M., Scacheri, P.C. Marinis, J.M., Harhaj, E.W., Scacheri, P.S., Matesic, L.M. and D.W. Abbott (2009) “ITCH K63-ubiquitinates the NOD2-binding protein, RIP2, to influence inflammatory signaling pathways.” Current Biology. 19:1255-1263.