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Susan Gunst, Ph.D.

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Professor

Department of Cellular & Integrative Physiology
Indiana University School of Medicine
635 Barnhill Drive, Room 313
Indianapolis, Indiana 46202-5120

E-mail: sgunst @ iupui.edu
Phone: 317-274-4108
Facsimile: 317-274-3318

Education / Training

  • 1973, B.A. in Biology, Brown University, Providence, Rhoad Island
  • 1979, Ph.D. in Physiology, Johns Hopkins University, Baltimore, Maryland
  • 1979-82, Postdoctoral Fellowship, Mayo Clinic and Foundation,
     Rochester, Minnesota

Research Biography Summary

Personal Statement

Research in my laboratory has been focused on the study of airway smooth muscle and airway physiology for over 25 years. My research has centered on the regulation of smooth muscle contractility and phenotype, and particularly on the roles of adhesion junction proteins and actin dynamics in determining airway smooth muscle functions in response to environmental stimuli such as the mechanical forces that occur during breathing and contractile and inflammatory stimuli. My laboratory has extensive expertise in the use of molecular approaches to study the signaling pathways and cytoskeletal processes that regulate the physiologic and phenotypic properties of airway smooth muscle tissues. These techniques have enabled us to evaluate the roles of specific proteins in the physiologic processes of airway smooth muscle while maintaining the cells in their normal cellular environment. Our studies have led us to propose a new model for the regulation of smooth muscle contraction that incorporates the roles of actin polymerization and dynamic changes in cytoskeletal organization in addition to actomyosin crossbridge activation. We have also demonstrated that integrin associated adhesion proteins interact with signaling pathways activated by inflammatory mediators to modulate inflammatory responses. We have extended our studies to animal models to evaluate the effects of mechanical forces and actin regulatory proteins on airway properties and airway responsiveness in vivo. We have also employed animal models to evaluate the potential of CPAP as a therapeutic tool for reducing airway hyperreactivity in asthma. These studies have recently been extended to human trials of CPAP as a potential therapy for asthma.

Contribution to Science

Research

The work in our laboratory is directed at determining the mechanisms by which the smooth muscle cells of the airways regulate their contractility and adapt to the mechanical stresses of their surrounding environment in the lung. The property of mechanical adaptation is important in the lung, because airway smooth muscle is continually subjected to stretch and shortening as the lung inflates and deflates during normal breathing. The stresses imposed on the airways as the lung inflates during breathing are known to play a major role in regulating airway tone and responsiveness in normal humans and animals. Studies of asthmatics suggest that the airway hyperresponsiveness characteristic of asthma may reflect abnormalities in the ability of the airway smooth muscle to adapt normally to the mechanical stresses placed on it during breathing.

A major focus of our lab has been the determination of the molecular mechanisms by which airway smooth muscle cells sense external mechanical forces and regulate signaling pathways that affect their contractility and physiologic properties. We have evidence that one of the primary mechanisms by which airway smooth muscle cells respond to changes in their mechanical environment is through the reorganization of the actin cytoskeleton. Cytoskeletal proteins and kinases associated with linking actin filaments to the membrane may also play a key role in regulating the organization of the actin cytoskeleton. Our studies have shown that several of these proteins, in particular focal adhesion kinase and paxillin, play an important role in transducing external mechanical signals into signaling pathways that regulate smooth muscle contractility and the organization of cell structure.

We are investigating the role of specific proteins that we believe to be involved in mechanical signaling and cytoskeletal organization. A primary approach that we are using is to manipulate the expression of these proteins in the smooth muscle using a transfection technique that is effective in intact tissues. Using this approach, we introduce genes encoding specific mutations in proteins of interest or down regulate the synthesis of targeted proteins with antisense. We then use an array of physiologic, biochemical, and cell biologic techniques to evaluate the effects of these genetic modifications on smooth muscle cell function, signaling pathways and structure. These techniques include: confocal microscopy to evaluate changes in the cellular localization of cytoskeletal proteins, biochemical assessments of protein associations and regulatory pathways, evaluation of the regulation of actin filament structure and assembly during contraction and relaxation, physiologic measurements of smooth muscle contractility, stiffness and responsiveness. Using these approaches, we hope to illuminate novel pathways by which the function of smooth muscle is regulated.

Grant Funding

NIH-NHLBI

R01 HL029289-22 (Gunst) 2/01/08-1/31/2012, “Smooth Muscle Mechanisms in Dynamic Airway Properties”, The major goals of this project are to evaluate the role of adhesion complex proteins in regulating the phenotype and contractility of airway smooth muscle. Role: Principal Investigator

R01 HL48522-13 (Tepper) 3/01/2008- 2/29/2012, “Airway Response: Mechanical Determinants and Maturation” The goals of this project are to evaluate molecular mechanisms for mechanical determinants of changes in airway responsiveness that occur during maturation. Role: Co-Principal Investigator

R01 HL074099 (Gunst) 7/01/2003-6/30/2013, “Regulation of Actin Dynamics in Airway Smooth Muscle” The major goal of this project is to evaluate mechanisms for the regulation of actin polymerization and depolymerization in airway smooth muscle during contractile stimulation and smooth muscle contraction. Role: Principal Investigator

Selected Recent Publications

Tang, D.D., D. Mehta and S.J. Gunst.  Mechano-sensitive tyrosine phosphorylation of paxillin and focal adhesion kinase in tracheal smooth muscle.
Amer J Physiol Cell Physiol 276: C250-C258, 1999.

Gunst, S.J.  Applicability of the Sliding Filament/Crossbridge Paradigm to Smooth Muscle.
Reviews of Physiology, Biochemistry and Pharmacology 134: 7-61, 1999. [Review] [255 references].

Mehta, D. and S.J. Gunst.  Actin polymerization stimulated by contractile activation regulates force development in canine tracheal smooth muscle.
J Physiol 519: 829-840, 1999.

Gunst, S.J. and D.D. Tang.  The contractile apparatus and mechanical properties of airway smooth muscle. Invited review.
Eur Respir J 15: 600-616, 2000.

Mehta, D., D.D. Tang, M. Wu, S. Atkinson and S.J. Gunst.  Role of Rho in Ca2+-insensitive contraction and paxillin tyrosine phosphorylation in smooth muscle.
Am J Physiol Cell Physiol 279: C308-C318, 2000.

Tang, D.D. and S.J. Gunst.  Depletion of focal adhesion kinase by antisense depresses contractile activation of smooth muscle.
Am J Physiol Cell Physiol 280: C874-C883, 2001.

Gunst, S.J. and M-F Wu.  Plasticity in Skeletal, Cardiac, and Smooth Muscle. Selected Contribution: Plasticity of airway smooth muscle stiffness and extensibility: role of length-adaptive mechanisms.
J Appl Physiol 90: 741-749, 2001.

Gerthoffer, W.T. and S.J. Gunst.  Signal Transduction in Smooth Muscle; Invited Review: Focal adhesion and small heat shock proteins in the regulation of actin remodeling and contractility in smooth muscle.
J Appl Physiol 91: 963-972, 2001.

Tang, D.D., Mingfang Wu, A.M. Opazo-Saez and S.J. Gunst.  The focal adhesion protein paxillin regulates contraction in canine tracheal smooth muscle.
Journal of Physiology 542.2, 501-513, 2002.

2003
Ramchandani, R., X. Shen, S.J. Gunst and R.S. Tepper.  Comparison of elastic properties and contractile responses of isolated airway segments from mature and immature rabbits.
J Appl Physiol 95: 265-271, 2003. PubMed

Gunst, S.J., D.D. Tang and A. Opazo-Saez.  Cytoskeletal remodeling of the airway smooth muscle cell: a mechanism for adaptation to mechanical forces in the lung.
Respir Physiol Neurobiol. 137(2-3): 151-168, Sep 2003. PubMed

Gunst, S.J. and J.J. Fredberg.  Invited Review: The first three minutes: smooth muscle contraction, cytoskeletal events, and soft glasses.
J Appl Physiol 95: 413-425, 2003. PubMed

2004
Opazo-Saez, A.M., W. Zhang, Yidi Wu, C.E. Turner, D.D. Tang and S.J. Gunst. Tension development during contractile stimulation of smooth muscle requires recruitment of paxillin and vinculin to the membrane.
Am J Physiol Cell Physiol 286: C433-C447, 2004. PubMed

Gunst, S.J.  Actions by actin: reciprocal regulation of cortactin activity by tyrosine kinases and F-actin.
Biochem J (2004) 380 (e7–e8) (Printed in Great Britain).

Tang, D.D. and S.J. Gunst.  The Small GTPase Cdc42 Regulates Actin Polymerization and Tension Development during Contractile Stimulation of Smooth Muscle.
J Biol Chem, Vol. 279, Issue 50, 51722-51728, December 10, 2004. PubMed

2005
Zhang, W., Yidi Wu, Liping Du, D.D. Tang and S.J. Gunst.  Activation of the Arp2/3 complex by N-WASp is required for actin polymerization and contraction in smooth muscle.
Am J Physiol Cell Physiol 288: C1145-C1160, 2005. PubMed

Tang, D.D., Ying Bai and S.J. Gunst.  Silencing of p21-activated kinase attenuates vimentin phosphorylation on Ser-56 and reorientation of the vimentin network during stimulation of smooth muscle cells by 5-hydroxytryptamine.
Biochem J (2005) 388 (773-783). (Printed in Great Britain). PubMed

Tang, D.D., W. Zhang and S.J. Gunst.  The Adapter Protein CrkII Regulates Neuronal Wiskott-Aldrich Syndrome Protein, Actin Polymerization, and Tension Development during Contractile Stimulation of Smooth Muscle.
J Biol Chem, Vol. 280, Issue 24, 23380-23389, June 17, 2005. PubMed

Tepper, R.S., R. Ramchandani, E. Argay, L. Zhang, Z. Xue, Y. Liu and S.J. Gunst.  Chronic strain alters the passive and contractile properties of rabbit airways.
J Appl Physiol 98: 1949-1954, 2005. PubMed

Xue, Z., L. Zhang, R. Ramchandani, Y. Liu, V.B. Antony, S.J. Gunst and R.S. Tepper.  Respiratory system responsiveness in rabbits in vivo is reduced by prolonged continuous positive airway pressure.
J Appl Physiol 99: 677-682, 2005. PubMed

Gunst, S.J.  Does airway inflation stretch the bronchial mucosal membrane? Invited Editorial.
J Appl Physiol 99: 2059-2060, 2005. PubMed

2006
Zhang, W. and S.J. Gunst.  Dynamic association between alpha-actinin and ß-integrin regulates contraction of canine tracheal smooth muscle.
Journal of Physiology 572.3, pp. 659-676, 2006. PubMed

Abstracts - 2006
Zhao, R., Liping Du and S.J. Gunst.  Contractile and mechanical stimuli regulate cofilin phosphorylation (Cofilin-P) in tracheal smooth muscle (TSM) tissues.
FASEB Journal 20: A1241, 2006.

Fomin, V.P., A. Kronbergs, W. Zhang and S.J. Gunst.  The effect of protein kinase C (PKC) on force and intracellular Ca in uterine smooth muscle from pregnant women.
FASEB Journal 20: A1242, 2006.

2007
An, SS, TR Bai, JHT Bates, JL Black, RH Brown, V Brusasco, P Chitano, L Deng, M Dowell, DH Eidelman, B Fabry, NJ Fairbank, LE Ford, JJ Fredberg, WT Gerthoffer, SH Gilbert, R Gosens, SJ Gunst, AJ Halayko, RH Ingram, CG Irvin, AL James, LJ Janssen, GG King, DA Knight, AM Lauzon, OJ Lakser, MS Ludwig, KR Lutchen, GN Maksym, JG Martin, T Mauad, BE McParland, SM Mijailovich, HW Mitchell, RW Mitchell, W Mitzner, TM Murphy, PD Paré, R Pellegrino, MJ Sanderson, RR Schellenberg, CY Seow, PSP Silveira, PG Smith, J Solway, NL Stephens, PJ Sterk, AG Stewart, DD Tang, RS Tepper, T Tran and L Wang.
Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma.
Eur Respir J 29: 834-860, 2007. PubMed

Zhang, W., Yidi Wu, Chuanyue Wu, and S.J. Gunst.  Integrin-linked Kinase Regulates N-WASp-mediated Actin Polymerization and Tension Development in Tracheal Smooth Muscle.
J Biol Chem, Vol. 282, Issue 47, 34568-34580, November 23, 2007. PubMed

Abstract - 2007
Wu, Yidi, Y. Huang and S.J. Gunst.  Integrin Linked Kinase (ILK) modulates SmMHC expression in tracheal smooth muscle tissues by regulating the activity of Serum Response Factor (SRF).
FASEB Journal 21: 939.2, 2007.

2008
Zhang, W., and S.J. Gunst.  Interactions of Airway Smooth Muscle Cells with Their Tissue Matrix: Implications for contraction.
The Proceedings of the American Thoracic Society Jan;5(1): 32-39, 2008. PubMed

Xue, Z., L. Zhang, Y. Liu, S.J. Gunst, and R.S. Tepper.  Chronic inflation of ferret lungs with CPAP reduces airway smooth muscle contractility in vivo and in vitro.
J Appl Physiol Mar;104(3): 610-615, 2008.

Zhang, W. and S.J. Gunst.  Dynamics of cytoskeletal and contractile protein organization: An emerging paradigm for airway smooth muscle contraction.
In: Airway Smooth Muscle in Asthma and COPD: Biology and Pharmacology. Edited by KF Chung. Wiley Press, June 2008. Blackwell Bookshop

Gunst, S.J. and W. Zhang.  Review: Actin cytoskeletal dynamics in smooth muscle: a new paradigm for the regulation of smooth muscle contraction.
Am J Physiol Cell Physiol Sept;295(3): C576-587, 2008.

Kim, H.R., C. Gallant, P.C. Leavis, S.J. Gunst, and K.G. Morgan.  Cytoskeletal remodeling in differentiated vascular smooth muscle is actin isoform dependent and stimulus dependent.
Am J Physiol Cell Physiol Sept;295(3): C768-C778, 2008.

Wu, Y., Y. Huang, B.P. Herring, and S.J. Gunst.  Integrin-linked kinase regulates smooth muscle differentiation marker gene expression in airway tissue.
Am J Physiol Lung Cell Mol Physiol 295: L988-L997, 2008.

Zhao, R., L. Du, Y. Huang, Y. Wu, and S.J. Gunst.  Actin depolymerization factor/cofilin activation regulates actin polymerization and tension development in canine tracheal smooth muscle.
J Biol Chem Vol. 283, Issue 52, 36522-36531, December 26, 2008. PubMed

2009

Fomin, V.P., A. Kronbergs, S.J. Gunst, D. Tang, V. Simirskii, M. Hoffman, and R.L. Duncan.  Role of protein kinase C{alpha} in regulation of [Ca2+](I) and force in human myometrium.
Reprod Sci 16(1): 71-79, Jan 2009. PubMed

2010

Zhang W, L. Du, S.J. Gunst.  The Effects of the Small GTPase RhoA on the Muscarinic Contraction of Airway Smooth Muscle Result from its Role in Regulating Actin Polymerization.
Am J Physiol Cell Physiol 299(2):C298-306, Aug 2010. PubMed

2011

Huang Y, Zhang W, Gunst SJ.  Activation of vinculin induced by cholinergic stimulation regulates contraction of tracheal smooth muscle tissue.
J Biol Chem. 286(5):3630-3644, Feb 4, 2011. PubMed

Xue Z, Yu Y, Gao H, Gunst SJ, Tepper RS.  Chronic Continuous positive airway pressure (CPAP) Reduces Airway Reactivity In Vivo in an Allergen Induced Rabbit Model of Asthma.
J Appl Physiol. 2011 Apr 14. [Epub ahead of print] PubMed


Last update: 04/2016

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