Curt Sigmund, Ph.D (Full Member)
Professor, Departments of Medicine and Physiology , University of Iowa
Director, Transgenic and Gene Targeting Facility, University of Iowa
Director, Center on Functional Genomics of Hyperte, University of Iowa

http://www.int-med.uiowa.edu/Divisions/Cardiology/Directory/CurtSigmund.html

Research Interest    

Dr. Sigmund's laboratory is primarily interested in investigating the regulation of genes involved in cardiovascular homeostasis and in creating novel transgenic, knockin and knockout models of cardiovascular disease that will enable an exploration of how these genes regulate blood pressure. For the past 16 years, the group has been investigating the mechanisms whereby the renin-angiotensin system (RAS) regulates blood pressure in normal and pathological states. During this time, it has developed novel models with which to explore the importance of the RAS, which generates the potent vasopressor hormone angiotensin-II, in the kidney and brain. Given that the kidney and brain both express all RAS components at both the mRNA and protein levels and that these organs also have the ability to generate angiotensin-II locally, the group hypothesized that the local generation of angiotensin-II in these organs may provide local hemodynamic control independent of the endocrine (i.e. circulating) system, a concept that was highly controversial at the time. Using transgenic models in which angiotensinogen (the angiotensin-II substrate) was specifically targeted to one of these organs, the group conclusively demonstrated that the RAS of each organ reulates blood pressure therein. More recently, Dr. Sigmund's group began to explore the mechanism whereby the peroxisome proliferator activated receptor gamma (PPARgamma) transcription factor regulates blood pressure and vascular tone, making extensive use of viral gene delivery, transgenesis, dominant negative mutants, microarrays and computational biology. A member of a family of ligand-activated transcription factors with roles in many physiological processes, PPARgamma is the molecular target of the thiazolidinedione class of drugs used to treat patients with non-insulin dependent diabetes mellitus (type II diabetes) for severe hypertension. Using transgenic mice in which dominant negative mutants of PPARgamma are targeted to the vascular wall, the research group has provided evidence that PPARgamma serves to protect the vasculature, and that interfering with its function can lead to vascular dysfunction and hypertension.

Selected Publications:

Zhou, X., Davis, D.R., and Sigmund, C.D. The Human Renin Kidney Enhancer Is Required to Maintain Baseline Renin Expression but is Dispensable for Tissue-Specific, Cell-Specific and Regulated Expression. J. Biol. Chem., 281: 35296-35304, 2006.

Dickson, M.E., Zimmerman, M.B., Rahmouni, K., and Sigmund, C.D. The -20 and -217 Promoter Variants Dominate Differential Angiotensinogen Haplotype Regulation in Angiotensinogen-Expressing Cells. Hypertension 49: 631-639, 2007.

Sakai, K., Agassandian, K., Morimoto, S., Sinnayah, P., Cassell, M.D., Davisson, R.L., and Sigmund, C.D. Local Production of Angiotensin-II in the Subfornical Organ Causes Elevated Drinking. J. Clinical Investigation 117: 1088-1095, 2007.

Halabi, C.M., Beyer, A.M. de Lange, W.J., Keen, H.L., Baumbach, G.L., Faraci, F.M. and Sigmund, C.D. Interference with PPARgamma Function in Smooth Muscle Causes Vascular Dysfunction and Hypertension. Cell Metabolism. (in press) 2008.

Publications from Gene Therapy Center

Publications from PubMed