B. Paul Herring, Ph.D.
Graduate faculty member
Department of Cellular & Integrative Physiology
Indiana University School of Medicine
635 Barnhill Drive, Room MS 350E
Indianapolis, Indiana 46202-5122
E-mail: pherring @ iupui.edu
Education / Training
• 1983, B.Sc. in Biological Sciences, University of Leicester, England
• 1986, Ph.D. in Biochemistry, University of Bristol, England
• 1986-88, Postdoctoral Fellowship, Univesity of Texas Southwestern Medical Center, Dallas, Texas
Altered contractile protein expression and increased smooth muscle cell proliferation are characteristics of many vascular and pulmonary diseases. The long-term goal of research in my laboratory is to unravel the mechanisms regulating smooth muscle development and differentiation. To begin to accomplish this goal, the molecular mechanisms regulating smooth muscle-specific expression of telokin, a small myosin binding protein, are being elucidated. The cis-acting elements in the telokin promoter that regulate expression in different smooth muscle tissues are being identified in cultured cells, in transgenic mice and by cre-mediated excision of elements from the endogenous gene. Several factors that bind to these important regulatory elements have been identified and cloned. The roles played by these proteins in regulating the expression of telokin and other smooth muscle genes is being investigated using a combination of in vitro and in vivo approaches. In cultured cells expression of putative regulatory molecules is being altered by adenoviral mediated over expression or siRNA mediated knockdown and the subsequent effects on expression of smooth muscle-specific genes determined. To analyze the function of these proteins in vivo cell-specific knockouts of the proteins are being generated. We are particularly focusing on how fox proteins and myocardin cooperate to regulate gene expression in smooth muscle cells and on the role played by chromatin remodeling enzymes in this process. These studies will help unravel the complex network of interactions that ultimately result in smooth muscle differentiation and provide reagents that can be used to design smooth muscle-specific gene delivery systems.
A second area of research being investigated in the laboratory is aimed at understanding the roles of specific myosin light chain kinase (MLCK) isoforms in regulating smooth muscle patho-physiology. Unraveling the roles of MLCK isoforms in regulating smooth muscle contractility, motility and cell division is crucial to our understanding of many different vascular and pulmonary diseases, such as atherosclerosis, hypertension, restenosis following angioplasty, asthma and chronic obstructive pulmonary disease that are associated with alterations in smooth muscle physiology. Toward this goal we are analyzing the promoters within the mylk1 gene that regulate expression of the different MLCK isoforms in order to develop molecular strategies that will allow us to knockout individual MLCK isoforms in vivo and subsequently determine their physiological and pathophysiological functions.
The laboratory is affiliated with the Indiana Center for Vascular Biology and Medicine (ICVBM), the Indiana University Cancer Center, and also has close ties with the Wells Center for Pediatric Research.
Elmendorf (Herring Co-I)
3/15/09-1/31/13, NIH RO1 DK082773. “Mechanisms of Membrane-Based Insulin Resistance and Therapeutic Reversal Strategies”.
7/1/09-6/30/11, NIH RO1 HL085212. "Function of the 130kDa MLCK in vasculature physiology and pathophysiology".
9/30/01-6/30/12, RO1 DK61130. “Regulation of visceral smooth muscle-specific gene expression during development”.
More Detailed Description of
HERRING LAB RESEARCH
The long-term goal of research in our laboratory is to unravel the mechanisms regulating smooth muscle development and differentiation. Smooth muscle cells arise from diverse populations of precursor cells during embryonic development and the mechanisms that specify the smooth muscle cell phenotype in each of these populations of cells are largely unknown. Smooth muscle cells in adult tissues are normally quiescent, exhibit very low rates of division, and express high levels of contractile proteins and myofilaments. All differentiated, contractile smooth muscle is characterized by the presence of unique isoforms of contractile proteins such as smooth muscle alpha and gamma-actin, myosin heavy chain, caldesmon, calponin, SM22alpha and telokin. Many cardiovascular disorders such as hypertension, atherosclerosis and most endovascular procedures are associated with a change in the growth and differentiation state of smooth muscle. Similarly, pulmonary diseases such as chronic asthma and chronic obstructive pulmonary disease are associated with increased airway smooth muscle proliferation resulting in decreased airway caliber. In addition, obstructive diseases of the gut and urinary system result in increased smooth muscle cell hypertrophy and hyperplasia. The expression of smooth muscle contractile proteins is markedly attenuated during the de-differentiation and proliferation of smooth muscle that occurs under these pathological conditions. Determining the mechanisms that control smooth muscle differentiation is important for us to understand the pathology of these diseases and to develop new reagents that can be used to prevent or reverse these diseases.
Over-expression of myocardin or the myocardin related transcription factor Mkl1 (MRTFA, MAL) in several types of cells results in the induction of many genes characteristic of differentiated smooth muscle. This suggests that these factors can act as master regulators of the smooth muscle lineage. Clearly the myocardin family of transcription factors plays a key role in smooth muscle development, however, a number of key questions regarding their action remain unanswered. Two questions that our research is attempting to answer are: Why does myocardin activate only a subset of SRF-dependent genes? How does myocardin activate promoters that are in condensed, inactive chromatin?
Feng, Y and Herring, B.P. GATA-6 can act as a positive or negative regulator of smooth muscle-specific gene expression. (2005)
J. Biol. Chem. 280, 4745-4752.
Zhou, J. and Herring, B.P. Mechanisms responsible for the promoter specific effects of myocardin. (2005)
J. Biol. Chem. 280, 10861-10869.
El-Mounayri, O., Triplett, J.W., Yates, C.W., and Herring, B.P. Regulation of smooth muscle-specific gene expression by homeodomain proteins, Hoxa10 and Hoxb8. (2005)
J. Biol. Chem. 280, 25854-25863.
Triplett, J.W., Herring, B.P., and Pavalko, F.M. Adenoviral transgene expression enhanced by co-treatment with etoposide in cultured cells. (2005)
Biotechniques 39, 826-832.
Zhou, J., Hu, G., and Herring, B.P. Smooth muscle-specific genes are differentially sensitive to inhibition by Elk-1. (2005)
Mol. Cell Biol. 25, 9874-9885.
Khromov, A., Wang, H., Choudhury, N., McDuffie, M., Herring, B.P., Nakamoto, R., Owens, G., Somlyo, A.P., and Somlyo, A.V. Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca2+ and decreased cGMP-induced relaxation. (2006)
P.N.A.S. 103, 2440-2445.
Yin, F., Hoggatt, A.M., Zhou, J., and Herring, B.P. The 130-kDa Smooth Muscle Myosin Light Chain Kinase is transcribed from a CArG-box dependent Promoter within the Mouse MYLK Gene. (2006)
Am. J. Physiol. 290, C1599-C1609.
Herring, B.P., El-Mounayri, O., Gallagher, P.J., Yin, F., and Zhou, J. Regulation of myosin light chain kinase and telokin expression in smooth muscle. (2006)
Am. J. Physiol. Cell Physiol. 291, C817-C827.
Touw, K., Hoggatt, A.M., Simon, G., and Herring, B.P. Hprt-targeted transgenes provide new insights into smooth muscle-restricted promoter activity. (2007)
Am. J. Physiol. 292, C1024-C1032.
Zhang, M., Fang, H., Zhou, J., and Herring, B.P. A novel role of Brg1 in the regulation of SRF/MRTFA-dependent smooth muscle-specific gene expression. (2007)
J. Biol. Chem., Vol. 282, Issue 35, 25708-25716, 31 August 2007.
Herring, B.P. and Zhou, J. Editorial: mCAT Got YouR TEF? Circulation Research 101(9): 856-858, October 2007.
Wu, Y., Huang, Y., Herring, B.P., and Gunst, S.J. Integrin-linked kinase regulates smooth muscle differentiation marker gene expression in airway tissue.
Am J Physiol Lung Cell Mol Physiol 295: L988-L997, 2008.
Zhou, J., Blue, E.K., Hu, G., and Herring, B.P. Thymine DNA glycosylase represses myocardin-induced smooth muscle cell differentiation by competing with SRF for myocardin binding.
J. Biol. Chem. Vol. 283, Issue 51, 35383-35392, 19 December 2008.
Zhou J, Zhang M, Fang H, El-Mounayri O, Rodenberg JM, Imbalzano AN, and Herring BP. The SWI/SNF Chromatin Remodeling Complex Regulates Myocardin-Induced Smooth Muscle–Specific Gene Expression.
AHA - Arteriosclerosis, Thrombosis, and Vascular Biology 29: 921-928, 2009. Full Text · PDF.
Hu G, Wang X, Saunders DN, Henderson M, Russell AJ, Herring BP, and Zhou J. Modulation of myocardin function by the ubiquitin E3 ligase UBR5.
J Biol Chem. 285(16):11800-11809, Apr 16, 2010. PubMed
Rodenberg JM, Hoggatt AM, Chen M, Touw K, Jones RE, and Herring BP. Regulation of Serum Response Factor Activity and Smooth Muscle Cell Apoptosis by Chromodomain Helicase DNA-Binding Protein 8. Am J Physiol Cell Physiol. 299(5):C1058-C1067, Nov 2010. PubMed
Zhang, M., Chen, M., Kim, J-Y., Zhou, J., Jones, R.E., Tune, J.D., Kassab, G.S., Metzger, D., Ahlfeld, S., Conway, S.J., and Herring, B.P. SWI/SNF complexes containing Brahma or Brahma related gene 1 play distinct roles in smooth muscle development. (2011) Mol. Cell. Biol. 31, 2618-2631 PubMed
Zhang, L., Widau, R.C., Herring, B.P., and Gallagher, P.J. Delta-like ligand 1-Lysine613 regulates Notch signaling. (2011) BBA- Molecular Cell Research. 1813, 2036-43 PubMed
Touw, K., Chakraborty, S., Zhang, W., Obukhov, A.G., Tune, J.D., Gunst, S.J. and Herring, B.P. Altered calcium signaling in colonic smooth muscle of type 1 diabetic mice. (2012) Am. J. Physiol. GI and Liver. 302, G66-76http://ajpgi.physiology.org/content/302/1/G66.full.pdf
Penque, B.A., Hoggatt, A.M., Herring, B.P., and Elmendorf, J.S. Hexosamine Biosynthesis Impairs Insulin Action via a Cholesterolgenic Response. (2013) Mol. Endo. 27, 536-47 PubMed
Chen, M and Herring, B.P. Regulation of microRNAs by Brahma-related gene 1 (Brg1) in smooth muscle cells. (2013) J. Biol. Chem. 288, 6397-6408 PubMed