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Dr. Brown received his M.D. at Johns Hopkins and his house staff
training in internal medicine at Johns Hopkins Hospital and the
University of California San Francisco. Following chief medical
residency at the University of California Medical Center in San
Francisco, he obtained clinical pulmonary training at UCSF and
then research training in the Cardiovascular Research Institute,
UCSF. He currently serves as Assistant Chief, Pulmonary and
Critical Care Medicine Section, VAMC-San Francisco and was Acting
Chief from 2002-2004. Academic activities include laboratory
research, clinical education, and directing the chest clinic,
pulmonary function laboratory, and sleep apnea program at the VA.
He attends at the VA on the ICU team, pulmonary consultation
service, and chest clinic and received the 2003 UCSF Pulmonary
and Critical Care Medicine Outstanding Teaching Award and the
1997 VAMC-SF Outpatient Teaching Award. He serves on the
American Thoracic Society's Research Advocacy Committee.
Our laboratory has had a long interest in
receptors and signal transduction pathways in airway smooth muscle
cells. Much of our early work focused on defining intracellular
pathways mediating receptor-mediated changes in contractile tone in
these cells, and we described some of the key intracellular
mechanisms by which beta-adrenergic agonists induce relaxant
responses. Subsequently, we changed our focus to the study of
hyperplasia of airway smooth muscle cells and, working in
collaboration with George Caughey, found that tryptase, a serine
proteinase that is abundantly expressed in mast cell granules, is a
potent mitogen for cultured airway smooth muscle cells.
My laboratory now focuses on attempts to define the cellular
mechanisms for tryptase-induced mitogenesis in cultured human
airway smooth muscle and lung fibroblast cells. Our recent
findings have established that mitogenic responses may occur via
either protein cleavage, mediated by tryptase's catalytic site, or
via nonproteolytic actions, likely involving binding of the
tryptase tetramer to specific sites on the smooth muscle or
fibroblast cell. Mechanisms under consideration include tryptase's
proteolytic cleavage at or near the cell surface of G-protein
coupled proteinase-activated receptors or matrix metalloproteinases
and binding of glycan residues on the tryptase tetramer to members
of the mannose family of receptors. We also are pursuing relevant
intracellular signals and have established that tryptase's mitogenic
effects require activation of both the p44/p42 MAP kinase and PI
3-kinase/Akt pathways in some respiratory cells. Taken together,
the findings may be relevant to two respiratory disorders in which
mast cells abound, namely asthma, where thickening of the airway
smooth muscle layer is a prominent feature, and pulmonary fibrosis.
Adding interest to this work are demonstrations from other
laboratories that tryptase has mitogenic effects on a variety of
other cell types and thus may have broad roles in growth and
development at sites where mast cells are found.
Brown, J.K., Hollenberg, M.D., Jones, C.A.: Tryptase activates
phosphatidylinositol 3-kinases proteolytically independent from
proteinase activated receptor-2 in cultured dog airway smooth
muscle cells. Am. J. Physiol.: Lung Cell. Mol. Physiol. 2005
Sep 9; [Epub ahead of print]. (abstract)
Brown, J.K., Jones, C. A., Rooney, L. A.,
Caughey, G.H., Hall, I. P.: Tryptase’s strong mitogenic effects
in cultured human airway smooth muscle cells are via nonproteolytic
actions. Am. J. Physiol: Lung Cell. Mol. Physiol. 2002;
282: L197-L206. (abstract)/(full
text)
Brown, J. K., Jones, C. A., Rooney, L. A., and Caughey, G. H.:
Mast cell tryptase activates extracellular-regulated kinases (p44/p42)
in airway smooth muscle cells: importance of proteolytic events,
time course, and role in mediating mitogenesis. Am. J. Respir.
Cell Mol. Biol. 2001;24:146-154. (abstract)/(full
text)
Brown, J. K., Tyler, C. L., Jones, C. A., Ruoss, S. J., Hartmann,
T, and Caughey, G. H.: Tryptase, the dominant secretory granular
protein in human mast cells, is a potent mitogen for dog tracheal
smooth muscle cells in culture. Am. J. Respir. Cell Mol. Biol.
1995;13: 227-236. (abstract)
Baker, D. G., Don, H. F., and Brown, J. K.: Alpha-adrenergic and
muscarinic cholinergic inhibition of acetylcholine release in
guinea pig trachea: role of neuronal K+ channels. Am. J. Physiol:
Lung Cell. Mol. Physiol. 266:L698-L704, 1994. (abstract)
Baker, D. G., Don, H. F., and Brown, J. K.: N-type, omega-conotoxin-sensitive
calcium channels mediate electrically evoked acetylcholine release
in guinea pig trachea. Am. J. Physiol.: Lung Cell. Mol. Physiol.
264:L581-L588, 1993. (abstract)
Madison, J.M. and Brown, J.K.: Differential inhibitory effects
of forskolin, isoproterenol, and dibutyryl-cyclic AMP on phosphoinositide
hydrolysis in canine tracheal smooth muscle. J. Clin. Invest.
82:1462-1465, 1988. (abstract)
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