Colin David Funk |
Professor of Physiology and Biochemistry B.Sc.(Hons)(Queen's), Ph.D.(McGill), CCFP (University of Pennsylvania) Queen's University Botterell Hall, Rm 445 Kingston Ontario, K7L3N6 Canada (613) 533-3242 Fax: (613) 533-6880 funkc@post.queensu.ca |
Molecular, Cellular, & Physiological Study of Cardiovascular Inflammation
Eicosanoids are a class of lipid-derived
molecules including leukotrienes, prostaglandins and isoprostanes that are
formed enzymatically by lipoxygenase enzymes, prostaglandin H synthases
(cyclooxygenases) or non-enzymatically by free radical-catalyzed lipid
peroxidation. These molecules have potent biological activities on platelets,
blood vessels and most organ systems, exerting their actions via G
protein-coupled receptors (GPCR's) or peroxisomal proliferator-activated
receptors (PPAR's). My laboratory is focusing on characterizing these
arachidonic acid pathways in terms of structure/function of key enzymes, cell
biology (intracellular trafficking of arachidonic acid cascade components) and
(patho)physiological (gene inactivation in embryonic stem cells and transgenic
mice) processes. Mouse models of cardiovascular disease are currently being
studied to define roles of lipoxygenases and leukotriene receptors.
PROJECT 1 To
develop a specific genomics/proteomics/lipidomics platform for the eicosanoid
system to evaluate (patho)physiological status and diagnostic patterns in
health and disease.
PROJECT 2 To
define the biological significance of endogenous cannabinoid-derived novel
prostaglandin glycerol ester compounds and to distinguish between
cyclooxygenase isozyme functions by the use of induced mutant “knock-in” mice.
PROJECT 3 To
understand the roles of lipoxygenase enzymes in atherosclerosis with the view
to developing and testing specific inhibitors in prevention of cardiovascular
disease.
PROJECT 4 To elucidate the 3D structure
and cellular dynamics of human 5-lipoxygenase, the initial enzyme in
leukotriene biosynthesis, with the view of developing a new generation of
specific anti-inflammatory drugs.
PROJECT 5 To
define the roles of cysteinyl leukotriene receptor subtypes in cardiovascular
regulation using transgenic and knockout mice and the biochemical signaling
pathways with the aim of creating novel CysLT2 receptor antagonists.
Chen, X-S.,
Sheller, J.R., Johnson, E.N., and Funk, C.D. Role of leukotrienes revealed by
targeted disruption of the 5-lipoxygenase gene. Nature 372: 179-182 (1994).
Johnson, E.N.,
Brass, L., and Funk, C.D. Increased platelet sensitivity to ADP in mice lacking
platelet-type 12-lypoxygenase. Proc. Natl. Acad. Sci. USA, 95: 3100-3105
(1998).
Kennedy, C.R.J.,
Zhang, Y., Brandon, S., Guan, Y., Coffee, K., Funk, C.D., Magnuson, M.A.,
Oates, J.A., Breyer, M.D., and Breyer, R.M. Salt-sensitive hypertension and
reduced fertility in mice lacking the prostaglandin EP2 receptor. Nature
Medicine, 5: 217-220 (1999).
Cyrus, T., Witztum,
J.L., Rader, D.J., Tangirala, R.K., Fazio, S., Linton, M.F., and Funk, C.D.
Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apoE
deficient mice. J. Clin. Invest. 103: 1597-1604 (1999).
Huang, J.T., Welch,
J.S., Ricote, M., Binder, C., Willson, T.M., Kelly, C., Witztum, J.L., Funk,
C.D., Conrad, D., and Glass, C.K. Interleukin-4-dependent production of PPAR
ligands in macrophages by 12/15-lipoxygenase. Nature, 400: 378-382 (1999).
Chen, X-S. and
Funk, C.D. The N-terminal "beta-barrel" domain of 5-lipoxygenase is
essential for nuclear membrane translocation. J. Biol. Chem. 276: 811-818
(2001).
Hui, Y., Yang, G.,
Galczenski, H., Copeland, N.G., Gilbert, D.J., Jenkins, N.A., and Funk, C.D.
The murine cysteinyl leukotriene 2 (cysLT2) receptor: cDNA and genomic cloning,
alternative splicing, and in vitro characterization. J. Biol. Chem., 276,
47489-47495 (2001).
Funk, C.D.
Prostaglandins and leukotrienes: advances in eicosanoid biology. Science, 294,
1871-1875 (2001).
Kulkarni, S., Das,
S., Funk, C.D. Murray, D., and Cho, W. A molecular basis of specific
subcellular localization of the C2-like domain of 5-lipoxygenase. J. Biol.
Chem. 277, 13167-13174 (2002).
Miller, Y.I., Worrall, D.S., Funk, C.D., Feramisco, J.R. and Witztum, J.L. Actin polymerization in macrophages in response to oxidized LDL and apoptotic cells: role of 12/15-lipoxygenase and phosphoinositide 3-kinase, Mol. Biol. Cell, 14, 4196-4206 (2003).
Yang, G., Haczku, A., Martin, V., Chen, H., Galczenski, H., Tomer, Y., Van Beisen, C.R., Evans, J.F., Panettieri, R.A., and Funk, C.D. Transgenic smooth muscle expression of the human CysLT1 receptor induces enhanced responsiveness of murine airways to leukotriene D4. Am. J. Physiol. (Lung Cellular and Molecular Physiology), in press (May 2004).
