MESSAGE FROM THE CHIEF
Hobart W. Harris, M.D., M.P.H.
Professor of Surgery
Chief, Division of General Surgery
Eileen F. Grady, Ph.D.
Associate Professor of Surgery
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: 415-502-7920 or 415-476-6978
Fax: 415-476-0936
Education
- B.A. (Biology and Theology), Fordham University, 1970-1974
Postdoctoral Training
- Ph.D. (Experimental Pathology, Cellular Immunology), University of California, San Francisco School of Medicine, 1975-1982
Research Interests
The regulatory mechanisms by which G protein coupled receptors (GPCRs) in the gut mediate both short- and long-term effects. Short-term effects of neuropeptides include neurotransmission and neurogenic inflammation. I am mainly studying neurogenic inflammation, in which sensory nerves are stimulated to release pro-inflammatory peptides. Thus, I am studying neuropeptide or protease induced receptor activation (i.e., substance P and CGRP, or tryptase, trypsin), internalization and recycling of their G protein coupled receptors in cells and in intact animals. I am particularly interested in the effects of degradative enzymes in the regulation of responsiveness to neuropeptides. I study this inflammation in the gut and pancreas using rats and transgenic mice in which the appropriate receptors, peptides, and the enzymes that degrade these peptides have been deleted (i.e. neurokinin 1 receptor (NK-1R), proteinase activated receptor-2 (PAR2), substance P, neutral endopeptidase, dipeptidyl peptidase I). Long-term effects of neuropeptides include chronic inflammation and pain. The mechanisms of desensitization, resensitization and down regulation must be examined to understand how some cells rapidly recover responsiveness even in the continued presence of ligand. Here the half life of a receptor, the selection process that regulates lysosomal sorting of a recycling receptor, and the number of times a particular receptor can signal to fresh ligand are key. I hope to understand in the intact animal: a) how regulation of responsiveness of GPCRs alters inflammation in the pancreas and gut; and b) how despite agonist induced desensitization, organs can maintain responsiveness to fresh ligand, leading to a continuous effect, such as gut motility.
Biography
Eileen F. Grady, Ph.D. is an Associate Professor in the Department of Surgery at the University of California, San Francisco. Her research laboratory is in the UCSF Center for the Neurobiology of Digestive Diseases. Her research focuses on neuropeptides (substance P and calcitonin gene related peptide) that are involved in intestinal inflammation using cells and mice in which proteins regulating responses to these peptides have been altered by genetic or pharmacological approaches. She examines responses to these peptides and inflammatory insults (C. difficile Toxin A, the IBD model of IL10-/- mice treated with piroxicam) in the context of modified levels of (1) receptors such as the neurokinin 1 receptor, the calcitonin-like receptor and protease activated receptor 2; (2) channels such as transient receptor of the vanilloid type 1, 4, and A1; (3) enzymes such as neutral endopeptidase, endothelin-converting enzyme 1, tryptase, and trypsin 4; and (4) regulatory proteins, such as β-arrestin.
She is a recipient of the Thomas More Honors Program (1970-1972), the New York State Regents Fellowship and Incentive Award (1970-1974), the Graduate Division Regents Fellowship (1975-1978), the Patent Funds Grants for Thesis Work (1979-1981), Nominated for Excellence in Lab Instruction, Med I Teaching Awards (1997, 1998, 1999, 2000), and Nominated for A Major Contribution to Teaching by Med Student Class of 2003.
Dr. Grady is Principal Investigator of a Crohn’s & Colitis Foundation of America grant (through 2010) and an NIH RO1 grant (through 2008). She is also a Co-Investigator on three additional, active NIH grants.
Her work on regulatory mechanisms by which G protein coupled receptors (GPCRs) in the gut mediate both short term and long term effects, as well as other areas of interest, has been extensively published in peer-reviewed journals.
Selected Publications
First suggestion that TNF-α may have a regulatory role, since produced by Th cells
1. Leopardi E., Rosenau W. Production of alpha-lymphotoxin by human T-cell subsets. Cellular Immunology 83;73-82, 1984.
First report of cytoskeletal changes in target cells as a first step in target cell lysis
2. Leopardi E., Friend D., Rosenau W. Target cell lysis: Ultrastructural and cytoskeletal alterations. Journal of Immunology 133:3429-36, 1984.
First suggestion that adult neurons may be able to divide since some cells express N-myc
3. Grady E.F., Schwab M., Rosenau W. Expression of N-myc and c-src during the development of fetal human brain. Cancer Research 47:2931-36, 1987.
First reports of agonist-induced trafficking of neuropeptide receptors in cell lines and in vivo
4. Garland, A.M, Grady, E.F., Payan, D.G., Vigna, S.R., Bunnett, N.W. Agonist-induced internalization of the substance P (NK1) receptor expressed in epithelial cells. Biochemical Journal 303, 177-186, 1994.
5. 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.
6. Grady, E.F., Garland, A.G., Gamp, P.D., Lovett, M, Payan, D.G., Bunnett, N.W. Delineation of the endocytic pathway of substance P and its seven transmembrane domain NK1 receptor. Molecular Biology of the Cell 6, 509-524, 1995.
7. Grady, E.F., Gamp, P.D., Jones, E., Baluk, P., McDonald, D.M., Payan, D.G., and Bunnett, N.W. Endocytosis and recycling of neurokinin 1 receptors in enteric neurons. Neuroscience, 75 (4):1239-54, 1996.
First reports on the use of fluorescent neuropeptides to study receptor trafficking
8. Bunnett, N.W., Dazin, P.F., Payan, D.G., and Grady, E.F. Characterization of receptors using cyanine 3-labeled neuropeptides, Peptides 16:733-740, 1995.
9. Bunnett, N.W., Payan, D.G., Grady, E.F. Detection of naturally occurring receptors for gastrin releasing peptides and tachykinins using cyanine 3-labeled neuropeptides. Histochemical Journal 28:811-826, 1996.
First reports that deletion or inhibition of neuropeptide degrading enzymes results in exaggerated signaling and diseases
10. Lu B.; Figini M.; Emanueli C.; Geppetti P.; Grady E.F.; Gerard N.P.; Ansell J.; Payan D.G.; Gerard C.; Bunnett N. The control of microvascular permeability and blood pressure by neutral endopeptidase. Nature Medicine 3(8):904-7, 1997.
11. Sturiale, S., Barbara, G., Qiu, B.S., Figini M., Geppetti P., Gerard N., Gerard C., Grady, E., Bunnett, N., Collins, S. M. Neutral endopeptidase (EC3.4.24.11) terminates colitis by degrading substance P. Proceedings of the National Academy of Sciences 96(20):11653-11658, 1999.
12. Maa, J., Grady, E.F., Kim, E.H., Yoshimi, S.K., Hutter, M.H., Bunnett, N.W., Kirkwood, K.S. NK-1 receptor desensitization and neutral endopeptidase terminate SP-induced pancreatic plasma extravasation. American Journal of Physiology. 279:G726-G732, 2000.
13. Kirkwood, K.S., Bunnett, N.W., Maa, J., Castagliuola, I., Liu, B., Gerard, N., Zacks, J., Pothoulakis, C., Grady, E.F. Deletion of neutral endopeptidase exacerbates intestinal inflammation induced by Clostridium difficile toxin A. American Journal of Physiology 281:G544-551, 2001.
Report of novel interactions between G-protein coupled receptors
14. Schmidlin, F., Dery, O., Bunnett, N.W., Grady, E.F. Heterologous regulation of signaling and trafficking of G-protein coupled receptors: interactions between the neurokinin 1 and 3 receptors. Proceedings of the National Academy of Sciences USA 99(5);3324-9,2002.
Use of antibodies to localize both components (CLR, RAMP1) of the rat CGRP1 receptor.
15. Cottrell, G.S., Roosterman, D., Marvizon, J.C., Song, B., Wick, E., Pikios, S., Wong, H., Berthelier, C., Tang, Y., Sternini, C., Bunnett, N.W., Grady, E.F. Localization of calcitonin receptor-like receptor and receptor activity modifying protein 1 in enteric neurons, dorsal root ganglia, and the spinal cord of the rat. Journal of Comparative Neurology 490(3):239-55, 2005.
First report that enzymes that trigger PAR2 participate in Clostridium difficile Toxin A-induced enteritis.
16. Cottrell, G.S., Amadesi, S., Pikios, S., Camerer, E., Willardsen, A., Murphy, B.R., Caughey, G.H., Wolters, P.J., Coughlin, S.R., Peterson, A., Knecht, W., Pothoulakis, C., Bunnett, N.W., Grady, E.F. Protease-activated receptor 2, dipeptidyl peptidase I, and proteases mediated Clostridium difficile Toxin A enteritis. Gastroenterology, 2007, 132(7):2422-37.