Nigel W. Bunnett, Ph.D.
Professor of Surgery and Physiology
Vice-Chair of Research, Department of Surgery
Director, UCSF Center for the Neurobiology of Digestive Diseases
Contact Information
UCSF Center for the Neurobiology of Digestive Diseases
Department of Surgery
513 Parnassus Avenue, Room S-1268
Campus Box 0660
San Francisco, CA 94143-0660
Tel: 415-476-0489 or 415-476-6978
Fax: 415-476-0936
Education
- B.Sc. (Animal Physiology and Nutrition [First Class Honors]), University of Leeds, England, UK (1978)
Fellowships
- Research Fellow, Department for Medicine and Center of Ulcer Research and Education, UCLA School of Medicine and VA Wadsworth Hospital Center, Los Angeles (1982-1983)
- Postdoctoral Research Fellow, Department of Animal Physiology and Nutrition, the University of Leeds, Leeds, England, UK (1983-1985)
Postdoctoral Training
- Ph.D., Institute of Animal Physiology, Babraham and Darwin College, Cambridge University, England, UK (1981)
Research Interests
My laboratory studies the mechanisms that switch-on and switch-off inflammation and pain. Inflammation protects against infection, and the sensation of pain allows organisms to avoid stimuli that would otherwise cause injury. However, inflammation must be tightly controlled since dysregulated, exaggerated inflammation causes disease and pain. The mechanisms that initiate and terminate inflammation and pain are poorly understood, and consequently the therapies are inadequate and often associated with detrimental side effects. Our work focuses on the role of proteolytic enzymes as “molecular switches†that initiate and terminate signaling by mediators of inflammation and pain. Proteases that act at the cell-surface and in endosomes, lysosomes and proteasomes cleave neuropeptides, G-protein coupled receptors and ion channels and thereby control signaling by major mediators of inflammation and pain transmission. Serine proteases from the circulation, inflammatory cells, epithelial tissues and the nervous system, which are generated and released during injury and inflammation, signal to sensory nerves by cleaving protease-activated receptors. Receptor activation stimulates the release of neuropeptides, which cause neurogenic inflammation of peripheral tissues and mediate nociceptive transmission in the spinal cord. Activation also causes hyperexcitability of neurons, in part by sensitizing ion channels in including members of the large family of transient receptor potential channels. Metalloendopeptidases, which are anchored to membranes at the cell-surface and in endosomes, process neuropeptides that mediate inflammation and pain transmission, and can thereby initiate and terminate inflammatory and nociceptive signaling. Enzymes such as neprilysin degrade neuropeptides at the cell-surface, and together with proteins that mediate receptor desensitization, such as arrestins, terminate neuropeptide signaling. Other peptidases that are present in endosomes, exemplified by endothelin-converting enzyme-1, cleave endocytosed neuropeptides, thereby allowing recycling of receptors and resensitization of inflammation and pain transmission. Proteases in lysosomes and proteasomes degrade receptors and ion channels to irrevocably terminate their ability to signal. Ubiquitin ligases covalently modify receptors and channels and thereby direct proteins to lysosomes and proteasomes, where proteolysis terminates signaling. Deubiquitinating proteases in endosomes reverse this process, allowing receptors and channels to escape degradation and continue to signal. We seek to discover the mechanisms that switch inflammation and pain on and off through studies at the molecular, cellular and organismal level. An understanding of the mechanisms that initiate and terminate inflammation and pain will provide insights into new therapies for prevalent and debilitating human diseases. The major general question of our work is: “What are the mechanisms that initiate and terminate neurotransmission of neurogenic inflammation and pain?†Specific questions include: 1) What protease cascades are activated during tissue injury and inflammation? 2) How do proteases signal to sensory neurons, activate/sensitize transient receptor potential channels, and initiate neurogenic inflammation and hyperalgesia to thermal and mechanical stimuli? 3) How do endosomal peptidases regulate the activity and trafficking of neuropeptide receptors? and 4) What are the mechanisms that target protease-activated receptors, neuropeptide receptors, and transient receptor potential ion channels to and from the plasma membrane?
Biography
Nigel W. Bunnett, Ph.D. is a Professor in the Departments of Surgery and Physiology at the University of California, San Francisco, as well as Vice-Chair for Research in the Department of Surgery at UCSF. He is also the Director of the UCSF Center for the Neurobiology of Digestive Diseases.
His research examines the basic mechanisms by which inflammation causes pain, at the molecular, cellular and whole animal level, to investigate why certain inflammatory agents cause sustained pain responses that persist long after the inflammation is resolved. His program involves extensive interactions amongst basic scientists and surgeons.
He is a recipient numerous awards. From the University of Leeds: Crabtree Prize, July 1976; Two prizes from the Flour Advisory Bureau, July 1977; Seton prize, July 1978; British Oil and Cake Prize, July 1978; and Medal for the Best Student in Agricultural Sciences, July 1978. From the University of California, San Francisco: Nominated for award in "Excellence in Small Group Instruction", 1991, 1992; Nominated for award in "Outstanding Lecture Series", 1992; 1994, 1996, 1997, 1998; Nominated for Kaiser Award for "Excellence in Teaching", 1994, 2002; Nominated for "Major Contribution to Teaching", 1994, 1996, 1997, 1998; Recipient of award for "Major Contribution to Teaching", 1995; Nominated for "Pre-clinical Faculty Teaching Awardâ€, 2001; Nominated for "Outstanding Lecture Series and Educatorâ€, 2003, 2004, 2006, 2007; and Recipient of Award for “Excellence in Innovative Curricular Design and Program Development†and “Excellence in Direct Teachingâ€, 2006. Other awards include: Award for best paper in Journal of Gastroenterology, 1995; The Novartis Neurogastroenterology Award, 1999; The Intestinal Disease Research Lecture Award, Calgary University, 2000; Julius Stone Lecturer 2000; Society of Investigative Dermatology, 2000; NIH MERIT Award, NIDDK, 2000; R.W. Johnson Focused Giving Grant, 2000; Jansen Award for Basic Research in Gastroenterology, 2001; Canada Research Chair (Chair of Pharmacology, McGill University), 2001 (declined); Victor Mutt Medal for Research in Regulatory Peptides, 2002; and Member of Clinical and Integrative Gastrointestinal Pathobiology Study Section, 2005-2009.
His work on the basic mechanisms by which inflammation causes pain has been extensively published in a wide variety of peer-reviewed journals. His curriculum vitae currently cites well over 200 published and in press articles, as well as 27 book chapters to date.
Dr. Bunnett is currently Principal Investigator on two RO1 NIH Grants, one T32 NIH Training Grant, one R37 NIH Merit Award, and one NIH Shared Equipment Grant. In addition, he is Co-Investigator on two R01 NIH grants. He also has industry contracts with Genencor International, Astra-Zeneca, Rigel Pharmaceuticals, Inc., Pfizer, Kinexis, Catalyst, and Rinat.
Selected Publications
Report of microdialysis use in peripheral tissues to examine release of inflammatory mediators in the interstitial fluid.
1. Bunnett, N.W., Walsh, J.H., Debas, H.T., Kauffman, G.L., Golanska, E.M. Measurement of prostaglandin E2 in interstitial fluid from the dog stomach after feeding and indomethacin. Gastroenterology 85, 1391-1398, 1983. Reports of agonist-induced trafficking of neuropeptide receptors in vivo.
2. Bowden. J.J., Garland, A.M., Baluk, P., Lefevre, P., Grady, E.F., Vigna, S.R., Bunnett, N.W., McDonald, D.M. Direct observation of substance P-induced internalization of neurokinin 1 NK1 receptors at sites of inflammation. Proceedings of the National Academy of Sciences 91, 8964-8968, 1994.
3. Sternini, C., Spann, M., Anton, B., Keith, D.E., Bunnett, N.W., Von Zastrow, M., Evans, C., Brecha, N. Agonist selective endocytosis of mu opioid receptor by neurons in vivo. Proceedings of the National Academy of Sciences 93, 9241-9246, 1996.
Reports that β-arrestin-dependent trafficking species the subcellular localization and function of MAP kinases.
4. DeFea, K., Zalevsky, J., Thoma, M., Déry, O., Mullins, R.D., Bunnett, N.W. b-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targetting of activated ERK1/2. Journal of Cell Biology 148, 1267-1282, 2000.
5. DeFea, K.A., Vaughn, Z.D., O’Bryan, E.M., Nishijima, D., Déry, O., Bunnett, N.W. The proliferative and anti-apoptotic effects of substance P require formation of a β-arrestin-dependent scaffolding complex. Proceedings of the National Academy of Sciences 97, 11086-11091, 2000.
Reports that proteases signal to epithelial cells by specific receptors.
6. Kong, W., McConalogue, K., Khitin, L.M., Hollenberg, M.D., Payan, D.G., Böhm, S.K., Bunnett, N.W. Luminal trypsin may regulate enterocytes through proteinase-activated receptor-2. Proceedings of the National Academy of Sciences 94, 8884-8889, 1997.
7. Corvera, C.U., Déry, O., McConalogue, K.M., Böhm, S.K., Khitin, L.M., Kong, W., Caughey, G.H., Payan, D.G., Bunnett, N.W. Mast cell tryptase regulates colonic myocytes through proteinase-activated receptor-2. Journal of Clinical Investigation 100, 1383-1393, 1997.
8. Nguyen, T.D., Moody, M.W., Okolo, C., Steinhoff, M., Bunnett, N.W. Trypsin activates ion channels in non-transformed dog pancreatic duct epithelial cells through proteinase-activated receptor 2. Journal of Clinical Investigation 103, 261-269, 1999.
Reports that deletion of neuropeptide degrading enzymes results in exaggerated signaling and diseases.
9. Lu, B., Figini, M., Emanueli, C., Geppetti, P., Grady, E.F., Gerard, N.P., Ansel, J.C., Payan, D.G., Gerard, C, Bunnett, N.W. The control of microvascular permeability and blood pressure by neutral endopeptidase. Nature Medicine 8, 904-907, 1997.
10. Sturiale, S., Barbara, G., Qiu, B., Figini, M., Geppetti, P., Grady, E.F., Bunnett, N.W., Collins, S.M. Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P. Proceedings of the National Academy of Sciences 96, 11653-11658, 1999.
Reports that proteases can signal to the nervous system to cause neurogenic inflammation and pain.
11. Steinhoff, M., Vergnolle, N., Young, S.H., Tognetto, M., Ennes, E.H., Trevisani, M., Hollenberg, M.D., Wallace, J.L., Caughey, G.H., Mitchell, S.E., Williams, L.M., Geppetti, P., Mayer, E.A., Bunnett, N.W. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nature Medicine 6, 151-158, 2000.
12. Vergnolle, N., Bunnett, N.W., Sharkey, K.A., Brusse, V., Compton, S.J., Grady, E.F., Cirino, G., Gerard, N., Basbaum, A.I., Andrade-Gordon, P., Hollenberg, M.D., Wallace, J.L. Proteinase-activated receptor-2 and hyperalgesia: a novel pain pathway. Nature Medicine 7, 821-826, 2001.
Reports that metalloendopeptidases regulate trafficking and signaling of receptors in endosomes.
13. Roosterman, D., Cottrell, G.S., Padilla, B.E., Muller, L., Eckman, C.B., Bunnett, N.W. and Steinhoff, M. Endothelin-converting enzyme 1 degrades neuropeptides in endosomes to control receptor recycling. Proc Natl Acad Sci U S A 104, 11838-11843, 2007.
14. Padilla, B.E., Cottrell, G.S., Roosterman, D., Pikios, S., Muller, L., Steinhoff, M. and Bunnett, N.W. Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and -arrestins. J Cell Biol 179, 981-997, 2007.