Curt D. Sigmund, Ph.D.
        Professor of Medicine and
        Molecular Physiology & Biophysics

Office: Lab: Phone: Lab: FAX: Email: Website:

3181B MERF 3181 MERF (319) 335-7604 (319) 335-8926 (319) 335-5350 curt-sigmund@uiowa.edu Sigmund Lab

Research Interests

Molecular Mechanisms Regulating Transcription of the Renin Gene.
My laboratory is primarily interested in investigating the regulation of genes involved in cardiovascular homeostasis using both cell culture and transgenic model systems. We have been examining the regulation of the gene encoding a protein (renin) central to the regulation of blood pressure and water and electrolyte homeostasis. We have identified a strong enhancer of transcription 2.6 kb upstream of the mouse renin gene and its homolog 13.0 kb upstream of the human renin gene. This enhancer is a complex regulatory element consisting of the binding sites for at least 7 different transcription factors including NF-Y, RAR, RXR, CREM, CREB, USF-1 and USF-2. These transcription factors serve to both up-regulate and down-regulate renin expression in response to physiological cues. Using yeast one-hybrid analysis, we recently determined that Ear2, an orphan member of the nuclear hormone super-family, is a strong negative regulator of renin expression. It represses transcription by binding to the same site as RAR on the enhancer and may therefore compete with it for binding. We are currently interrogating the importance of steroid hormone receptor transcription factors in regulating renin expression using inhibitory RNAs (RNAi).

We have also generated a number of transgenic mouse models to examine the regulation of renin transcription. The most important model consists of a 160 kb P1 artificial chromosome (PAC) construct which contains the renin gene as well as the upstream PEPP3 and Kiss1 genes and the downstream FLJ10761 and Sox13 genes. The regulation of renin transcription from this construct is exquisitely tight, responding exactly as anticipated to physiological signals which normally regulate the renin gene. We are currently performing mutagenesis of each of the transcription factor binding sites in this PAC construct to assess their importance in tissue- and cell-specific expression of renin, its response to hormonal stimulation and its response to physiological signals. We are also determining if the enhancer influences the transcription of the nearby upstream and downstream genes.

Selected Publications

1. Keen, H.L., Ryan, M.J., Beyer, A., Mathur, S., Scheetz, T.E., Gackle, B.D., Faraci, F.M., Casavant, T.L., Sigmund, C.D. Gene Expression Profiling of Potential PPARγ Target Genes in Mouse Aorta Physiological Genomics. 18: 33-42, 2004.

2. Sakai, K., Chapleau, M.W., Morimoto, S., Cassell, M.D. and Sigmund, C.D. Differential Modulation of Baroreflex Control of Heart Rate by Neuron- vs. Glia-derived Angiotensin II. Physiological Genomics 20: 66-72, 2004.

3. Sherrod, M., Liu, X., Zhang, X., and Sigmund, C.D.: Nuclear Localization of Angiotensinogen in Astrocytes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288:R539-R546, 2005.