Pathobiology of smooth muscle, signal transduction, myosin, thin filament-associated protein caldesmon, smooth muscle cell differentiation, translational research
Description of Research
The major research focus in Dr. Chacko’s laboratory are:
Molecular/Cellular Mechanisms For Smooth Muscle Contractile Dysfunctions:
Our experiments to study the mechanisms for contractile dysfunctions are directed to understand the regulation of actomyosin ATPase and contraction in normal and pathological smooth muscles. Specifically, the roles of smooth muscle myosin isoforms, myosin light chain phosphorylation, and thin filament-associated proteins (caldesmon and calponin) in actin-myosin interaction and cross-bridge cycling are investigated.
Remodeling Of Urinary Bladder Smooth Muscle In Outlet Obstruction:
Molecular mechanisms for the regulation of actin-myosin interaction and contraction in normal and hypertrophied smooth muscle. A rabbit model for outlet obstruction is used to elucidate the mechanisms for altered contractility of the detrusor smooth muscle in men with outlet-obstruction in benign prostatic hyperplasia. This study is part of the George O'Brien Urology Research Center supported by a Center Grant from the National Institute for Diabetes, Digestive and Kidney Diseases (NIDDK), National Institute of Health (NIH).
Molecular Mechanisms For Erectile Function And Dysfunction In Men:
Cell and molecular biology of the contractile function of smooth muscle cells in the corpus cavernosum penis from normal rabbits and men with erectile dysfunctions. The present research focuses on the signal transduction pathway that is responsible for the GTP-mediated relaxation of the smooth muscle in the penis. In addition, we investigate the role of free radicals on the contractility of corpus cavernosum smooth muscle in alloxan-induced diabetes in rabbits.
Mechanisms For The Urinary Bladder Dysfunction In Diabetes:
Molecular and biochemical mechanisms for the altered contractility of the detrusor smooth muscle in diabetes are studied using streptozotocin-induced and alloxan-induced diabetes in rats and rabbits, respectively. The investigation includes the expression of isoforms of proteins (PK-C, MLCK, Rho-kinase, myosin, etc) involved contractile proteins and proteins involved in signal transduction.
Cytodifferentiation Of Smooth Muscle:
Differentiation of smooth muscle phenotypes during development. Transcriptional regulation of myosin isoforms in developing and pathological smooth muscle in the bladder wall is investigated.
Technical Approaches include expression of contractile proteins using a bacculovirus expression system, site directed mutagenesis, gene knockouts, in situ hybridization, immunohistochemistry, in vitro motility assay & enzymatic assays to study the actin-myosin interaction, and studies using fluorescent labeled proteins to study protein conformation during protein-protein interaction.
1. Studies on the signal transduction pathways in normal and pathological (erectile dysfunction, bladder smooth muscle hypertrophy in outlet obstruction and diabetes) urinary bladder and penile smooth muscle
2. Molecular mechanisms for caldesmon function and smooth muscle regulation using a new caldesmon-knockout mouse model
Shaohua Chang, Ph.D., Research Associate, Division of Urology, University of Pennsylvania Medical School
Erzsebet Polyak, Ph.D. Research Investigator
Edward LaBelle, Ph.D., Adjunct Associate Professor
Gina Northington, M.D., Ph.D.- Postdoctoral Fellow in Urogyenacology
Maureen Basha, Ph.D.- Postdoctoral Fellow
Andy Chang, M.D.- Postdoctoral Fellow in Pediatric Urology
Yongmu Zheng, M.D.- Research Specialist
Joseph Hypolite, B.S.- Research Specialist
Changolkar A;Hypolite J;DiSanto ME;Oates P;Wein AJ;Chacko S Diabetes-Induced Decrease in Detrusor Smooth Muscle Force is Associated with Oxidative Stress and Overactivity of Aldose Reductase Journal of Urology 173: 309-313, 2005.Zhang E, Stein R, Chang S, Zheng Y, Zderic SA, Wein AJ, and Chacko S Smooth Muscle Hypertrophy following Partial Bladder Outlet Obstruction is Associated with Overexpression of Non-Muscle Caldesmon Am J. Pathology 164: 601-612, 2004.Chang, S., Hypolite, J., Changolkar, A., Wein, AJ., Chacko, S. DiSanto, ME Increased contractility of diabetic rabbit copora smooth muscle in response to endothelin is mediated via Rho-kinase ² Int J Impot Res 15: 53-62, 2003.DiSanto ME, Stein R, Chang S, Hypolite JA, Zheng Y, Zderic S, Wein AJ, Chacko S. Alteration in the expression of myosin isoforms in detrusor smooth muscle following bladder outlet obstruction Am J Physiol Cell Physiol 285: C1397-410, 2003.Bing W, Chang S, Hypolite JA, DiSanto ME, Zderic SA, Rolf L, Wein AJ, Chacko S Obstruction-induced changes in urinary bladder smooth muscle contractility: A role for Rho-kinase Am J Physiol Renal Physiol 285: F990-7, 2003.Zheng, Y., Weber, W.T., Wang, S., Wein, A.J., Chacko, S., and DiSanto, M.E. Establishment of a phenotypically stable bladder myocyte cell line from hypertrophied detrusor smooth muscle Am. J. Physiol Cell Physiology 283: C373-82, 2002.Zhang EY;Stein R;Chang S;Zheng Y;Zderic SA;Wein AJ;Chacko S; Smooth muscle hypertrophy following partial bladder outlet obstruction is associated with overexpression of non-muscle caldesmon American Journal of Pathology 164(2): 601-612 : , 2004.Deng M, Mohanan S, Polyak E, Chacko S. Caldesmon is necessary for maintaining the actin
and intermediate filaments in cultured bladder smooth muscle cells.
Cell Motil Cytoskeleton. 2007 Sep 14 [Epub ahead of print] PMID: 17868135 [PubMed - as supplied by publisher]
: , 2007.Basha M, Labelle EF, Northington G, Wang T, Wein AJ, Chacko S. Functional significance of muscarinic receptor expression within the proximal and distal rat vagina. Sep 9 Am J Physiol Regul Integr Comp Physiol. : , 2009.Chang S, Hypolite JA, Mohanan S, Zderic SA, Wein AJ, Chacko S. Alteration of the PKC-mediated signaling pathway for smooth muscle contraction in obstruction-induced hypertrophy of the urinary bladder. Lab Invest. 89: 823-832, 2009.