Research Interests
My laboratory is focused on applying systems biology perspectives
to translational research for the discovery of novel diagnostics
and therapeutics for diseases. These approaches include studies in
humans, animal models of disease, and cell culture with particular
emphasis on signal transduction pathways and networks that
regulate
information flow, especially via phosphorylation. Using a
state-of-the-art
mass spectrometer with a novel combination of conceptual
approaches,
my laboratory has established global, quantitative methods for
both
protein levels and phosphorylation from cells and tissues in
animal
models of disease. More recently, this approach has been melded
collaboratively
with NMR-based metabolomics research and bioinformatics
integrative tools to construct predictive, hypothesis-generating models
that are iteratively refined by focused perturbation. These models then
extend the depth and value of the systems biology perspective of the
underlying physiology of normal and disease processes.
Specific project areas include:
- symmetric growth of human adult umbilical cord blood stem cells
for directed engineering into islet-like structures for a cure for
type 1 diabetes
- renal cortical complications of diabetic nephropathy in an animal
model of type 2 diabetes
- amelioration of learning and memory deficits in an animal model
of Alzheimer's Disease
- female reproductive dysfunction in response to hyperinsulinemia in cell models of insulin signaling
- systems biology approaches to health disparities in the Mexican
American population through community outreach programs
- dynamic regulation of the composition and phosphorylation of multiprotein complexes
- proinflammatory cytokines and chemokines in depression in patients with diabetes
- therapeutic and biomarker discovery and intervention in inflammation, cognitive
dysfunction, and depression
Selected Publications
- Haycock, J.W.; Levy, W.B.; Denner, L.A.; Cotman, C.W. Stimulus-secretion
coupling processes in brain: dependence on extracellular calcium
concentration. Neurosci. 4:1341-1346; 1979.
- Denner, L.A.; Wu, J.-Y. Two forms of rat brain glutamic acid decarboxylase differ
in their dependence on free pyridoxal phosphate. J. Neurochem.
44:957-965; 1985.
- Lickteig, R.; Shenoliker, S.; Denner, L.A.; Kelley, P.T. Regulation
of Ca2+/calmodulin-dependent protein kinase II by Ca2+/calmodulin-independent autophosphorylation.
J. Biol. Chem. 263:19232-19240; 1988.
- Denner, L.A.; Maxwell, B.L.; Weigel, N.L.; Schrader, W.T.; O'Malley, B.W. Phosphorylation
regulates progesterone receptor-mediated transcription. Science
250:1740-1743; 1990.
- Denner, L.A.; Schrader, W.T.; O’Malley, B.W.; Weigel, N.L. Hormonal
regulation and identification of chicken progesterone receptor
phosphorylation sites. J. Biol. Chem. 265:16548-16555; 1990.
- Cleek, R.L.; Rege, A.A.; Denner, L.A.; Eskin, S.G.; Mikos, A.G. Inhibition
of smooth muscle cell growth in vitro by an antisense oligodeoxynucleotide released
from poly(DL-lactic-co-glycolic acid) microparticles. J. Biomed.
Mater. Res. 35:525-530; 1997.
- Hickbottom, S.L.; Grotta, J.C.; Strong, R.; Denner, L.; Aronowski,
J. Nuclear factor-kappaB and cell death after experimental intracerebral hemorrhage
in rats. Stroke 30:2472-2477; 1999.
- Yeh, C.H.; Sturgis, L.; Haidacher, J.; Zhang, X.N.; Sherwood, S.J.; Bjercke, R.J.; Juhasz,
O.; Crow, M.T.; Tilton, R.G.; Denner, L. Requirement for p38 and
p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear
factor-kappaB transcriptional activation and cytokine secretion. Diab.
50:1495-1504; 2001.
- Zhang, Y.; Yu, J.; Unni, E.; Shao, T. C.; Nan, B.; Snabboon,
T.; Kasper, S.; Andriani, F.; Denner, L.; Marcelli, M. Monogene and polygene therapy
for the treatment of experimental prostate cancers by use of apoptotic
genes bax and bad driven by the prostate-specific promoter
ARR(2)PB. Hum. Gene Ther.20:2051-64; 2002.
- Jiang, J.D.; Denner, L.; Ling, Y.H.; Davis, A.; Wang, Y.; Li,
Y.; Roboz, J.; Want, L.G.; Perez-Soler, R.; Marcelli, M.; Bekesi,
G.; Holland, J.F. Double blockage of the cell cycle at G(1)-S transition
and M phase by 3-iodoacetomido benzoyl ethyl ester, a new type
of tubulin ligand. Can. Res. 62:6080-8; 2002.
- Urban RJ, Bodenburg YH, Jian J, Denner L, Chedrese J. Protein kinase C
iota enhances the transcriptional activity of the porcine P-450
side-chain cleavage insulin-like response element. Am J Physiol Endocrinol Metab 286:E975-E979,
2004.
- Flyvbjerg A, Denner L, Schrijvers BF, Tilton RG, Mogensen TH, Paludan SR, Rasch R.
Long-term renal effects of a neutralizing RAGE antibody in obese
type 2 diabetic mice. Diabetes 53:166-172, 2004.
- Schrijvers BJ, DeVriese AS, Tilton RG, Van de Voorde J, Denner L, Lameire NH, Flyvbjerg A.
Inhibition of vascular endothelial growth factor (VEGF) does not
affect early renal changes in a rat model of lean type 2 diabetes. Horm Metab Res 37:21-25,
2005.
- McGuckin CP, Forraz N, Baradez MO, Navran S, Zhao J, Urban R, Tilton R
and Denner L. Production of stem cells with embryonic characteristics
from human umbilical cord blood. Cell Prolif 38: 245-255, 2005.
- Jensen LJ, Denner L, Schrijvers BF, Tilton RG, Rasch R and Flyvbjerg A.
Renal effects of a neutralizing RAGE-antibody in long-term streptozotocin-diabetic
mice. J Endocrinol 188: 493-501, 2006.
- Forbus, J, Spratt H, Wiktorowicz J, Wu Z, Boldogh I, Denner L, Kurosky A,
Brasier RC, Luxon B and Brasier AR. Functional analysis of the
nuclear proteome of human A549 alveolar epithelial cells by HPLC-high
resolution 2-D gel electrophoresis. Proteomics 6: 2656-2672,
2006.
- Starkey JM, Haidacher SJ, Lejeune WS, Zhang Z, Tieu BC, Choudhary S,
Brasier AR, Denner LA and Tilton RG. Diabetes-induced activation
of canonical and noncanonical nuclear factor-{kappa} B pathways
in renal cortex. Diabetes: 1252-1259, 2006.