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Louis Philipson, M.D., Ph.D.Primary: Professor, Section of Endocrinology, Diabetes, and
Metabolism Secondary: Committee on Cellular and Molecular Physiology |
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Education:
Research SummaryThe goal of Dr. Philipson’s laboratory is to better understand how pancreatic ß-cells "know" when to secrete insulin and define defects in this process in diabetes that could be therapeutic targets. The main focus is the study of ion channels, metabolism, and mitochondria that together regulate intracellular calcium concentration and energy production and thereby regulate insulin secretion in pancreatic islet ß-cells. ß-cell calcium regulatory processes have been shown to be dysfunctional in several models of diabetes mellitus and hypoglycemia. One ongoing aim is to define the identity of the repolarizing K+ channels in ß-cells – responsible for the islet correlate of the T wave in the cardiac electrocardiogram. Dr. Philipson has found that Ca2+ oscillations in insulinoma cells and rat islets are suppressed by the endogenous voltage-dependent K+ channels and insulin secretion can be dramatically enhanced by blocking only one case of sulfonylurea-insensitive K+ channels. This project has resulted in the generation of a transgenic mouse which expresses a K+ channel- green fluorescent fusion protein in the pancreatic ß-cells, allowing the insulin-containing cells to be directly visualized in real time using fluorescence microscopy. These studies are also being pursued in human islets, as part of an overall study evaluating the secretagogue-induced calcium responses of human islets prepared for transplantation in collaboration with Dr. B. Hering (U. Minnesota). An important target is calcium channels in ß cells, and Dr. Philipson recently cloned, expressed and produced null mice for the novel Ca2+ channel termed alpha-1E (CACNA1E). This and other channels such as LTRPC7 are under investigation for their role in insulin secretion. Other ongoing projects have focused on the role of SK channels in ß cell oscillations, the relationship of islet gap-junctions to ß-cell calcium signaling in collaboration with Dr. Beyer, and novel subcellular targetted indicators for ions and IP3 release in collaboration with Dr. Roe. Dr. Philipson is co-director of the Human Islet Transplantation project at the University of Chicago, for which a new GMP-standard laboratory is under construction. Selected PublicationsSteiner, D.F.
Ed. "Landmark
Papers in Insulin Biosynthesis", Foreword by A. Lernmark, O.
Madsen,
and L.H.
Philipson. Current Medicine Group, Tamarina,
N.A.,
Kuznetsov, A., Rhodes, C.J.,
Bindokas, V.P., and Philipson,
L.H.
Inositol 1,4,5-Trisphosphate Dynamics and Intracellular Calcium
Oscillations in
Pancreatic ß-Cells. Diabetes,
54:3073-81, 2005 Yin, D., Tao,
J.,
Lee, D.D., Shen, J.,
Hara, M., Lopez, J., Kuznetsov, A., Philipson,
L.H. and Chong, A.S.
Recovery of islet
beta-cell function in streptozotocin- induced diabetic mice: an
indirect role
for the spleen. Diabetes, 55:
3256-63, 2006 Roe, M.W.,
Fiekers,
J.F., Philipson, L.H. and
Bindokas, V.P. Visualizing calcium signaling
in cells by digitized
wide-field and
confocal fluorescent microscopy. Methods
Mol Biol., 319: 37-66, 2006 Fridlyand, L.E.
and Philipson, L.H. Cold
climate genes and the prevalence of type 2 diabetes mellitus. Med.
Hypotheses, 67(5): 1034-41, 2006. Jacobson, D.A.,
Cho, J., Landa,
L.R., Tamarina, N.A., Roe, M.W., Buxbaum, J.D. and Philipson, L.H. The
Downstream
Regulatory Element Antagonistic Modulator Regulates Islet Prodynorphin
Expression. Am. J. Physiol.
Endocrinol. Metab., 291:E587-95, 2006. Gimi, B.,
Leoni, L., Oberholzer,
J., Braun, M., Avila, J.,
Wong, Y., Barbaro, B.,
Gangemi, A., Qi, M., Knechle, J., Doubleday, N., Doubleday, M.,
Churchill, T.,
Salehi, P., Philipson, L., Shapiro, J., Benedetti, E., Lakey, J., and
Oberholzer, J. Improved Outcomes in Islet Isolation and Transplantation
by the
Use of a Novel Hemoglobin-based O2 Carrier.
Am. J. Transplant.,
6:2861-70, 2006 Fridlyand,
L.E. and Philipson L.H.
Reactive species and early manifestation of insulin resistance in type
2
diabetes. Diabetes Obes Metab.,
8:136-45, 2006 Fridlyand,
L.E. and Philipson,
L.H. Oxidative reactive species in cell injury: mechanisms
in
diabetes
mellitus and therapeutic approaches. Ann.
N.Y. Acad Sci., 1066:136-51,
2006. Chong, A.S.,
Shen, J., Tao, J.,
Yin, D., Kuznetsov, A., Hara, M., and Philipson,
L.H. Reversal of
diabetes in
NOD mice without spleen-cell derived beta-cell regeneration. Science, 311(5768):1774-5, 2006 Philipson,
L.H.
and Dukes, I.D.
Commentary: K+ channels: Generating Excitement in Pancreatic
ß-Cells. In
Commentaries on Perspectives in Diabetes, Volume 2, Robertson, R.P.
Ed., American Diabetes Association,
p279-290
Kitiphongspattana,
K., Khan, T.A,,
Ishii-Schrade, K., Roe, M.W., Philipson,
L.H. and Gaskins, Jacobson, D.A., Weber, C.R., Bao, S., Turk, J. and Philipson, L.H. Modulation of the Pancreatic Islet beta-Cell-delayed Rectifier Potassium Channel Kv2.1 by the Polyunsaturated Fatty Acid Arachidonate. J. Biol. Chem., 282:7442-9, 2007. Jacobson, D.A.
and Philipson,
L.H. "TRP Channels of the Pancreatic Beta Cell," Chapter in "TRP
channels
in health and disease" in the series "Handbook
of Experimental
Pharmacology" Jacobson, D.A.,
and Philipson, L.H. Action
potentials and
insulin secretion: new insights into the role of Kv channels. Diabetes,
Obesity
and Metabolism, in press, 2007 Jacobson, DA.,
Kuznetsov, A., Lopez,
J.P., Kash, S., Ämmälä,
C.E. and Philipson, L.H. Stoy,
J.,
Edghill, E.L., Flanagan S.E.,
Ye, H., Paz V.P., Pluzhnikov, A., Below, J.E. Hayes, M.G. Cox, N.J.
Lipkind,
G.M., Lipton, R.B., Greeley,
S.A., Patch,
A.-M. Ellard, S. Steiner, D.F., Hattersley, A.T., Philipson, L.H. and
Updated 9/24/07. |
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