International Continence Society

BIOGRAPHICAL SKETCH
Provide the following information for the key personnel in the order listed for Form Page 2.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
Biosketch: Chacko, Samuel K., DVM, Ph.D.
NAME
Chacko, Samuel K., DVM, Ph.D. POSITION TITLE
Professor of Pathology, Director of Basic Urological Research, Division of Urology, Department of Surgery
University of Pennsylvania Medical Center

eRA COMMONS USER NAME
CHACKOSK
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)
INSTITUTION AND LOCATION DEGREE
(if applicable) YEAR(s) FIELD OF STUDY
Kerala Veterinary College, India B.V.Sc. (U.S. equiv. D.V.M.) 1963 Veterinary Medicine
University of Pennsylvania, Philadelphia, PA Ph.D. 1969 Experimental Pathology

1. Positions and Honors. List in chronological order previous positions, concluding with your present position. List any honors. Include present membership on any Federal Government public advisory committee.
   1/1/96- present. Director of Basic Urological Research, Div. of Urology, Univ. of Pa. School of Medicine
   1993-Present- Professor of Pathology (Secondary Appointment), Div. of Urology, Dept. of Surgery, Univ. of Pa. School of Medicine
   1981- Present- Professor of Pathology, Department of Pathobiology, Univ. of Pa. School of Vet. Medicine
   3/1/94 to 8/30/94 Visiting Scientist (on scholarly leave), Molecular Cardiology, NHLBI, NIH, Bethesda, MD
   1991 Visiting Scientist, Institute of Cytology, Russian Academy of Science, Leningrad, USSR
   1987-1988 Visiting Scientist (on Scholarly Leave) Section on Cell Biology & Biochemistry, NHLBI, NIH,
   1984-87 & 89-93 Chairman, Graduate Group in Pathology, Biomedical Graduate Pro., Univ. Of Pa
   1981 Visiting Professor, Institute of Physiology, School of Medicine, Univ. of Heidelberg, West Germany
   1983 Visiting Professor, University of Tokyo, Faculty of Medicine (Fogarty Intl. Senior Fellow)
   1974-1981 Assoc. Professor, Department of Pathology, Graduate School of Arts & Sciences, U of Penn.
   1975-1977 Experimental Pathologist (On scholarly) Molecular Cardiology Section, NHLBI, NIH
   1969-1974 Asst. Professor, Department of Pathobiology, Univ. of Pa School of Vet. Medicine
   1967-1969 USPHS Trainee Department of Pathobiology, University of Pennsylvania
   1966-1967 Instructor in Pathology, Comparative Cardiovascular Studies Unit, U of Pennsylvania
   Honors and Membership
   Beta Chapter, Phi Zeta, Membership in the Biophysical Society, American Society for Biological Chemistry, American Association of Investigative Pathology, Am. Urological Assoc., European Society for Impotence Research, and American Diabetes Association
   Senior Fogarty International Research Fellow,
   Lindback Award for Distinguished Teacher
   Editorial Boards- Journal of Urology, Neurourology & Urodynamics, and Journal of Molecular Urology
   Member, NIH Study Section NIDDK-D- 2004-2006
   Member, NIH Study Section UKGD-2005-
2. Selected peer-reviewed publications (in chronological order). Do not include publications submitted or in preparation. (Selected from over 100 publications)
   Chacko, S (1973) DNA synthesis, mitosis, and differentiation in cardiac myogenesis. Devel. Biol 35:37274
   Garfield, R. E., Chacko, S., and Blose, S. (1975) Phagocytosis by muscle cells. Lab. Invest. 33:418-427.
   Somlyo, A. P., Garfield, R. E., Chacko, S., and Somlyo, A. V. (1975) Golgi organelle response to the calcium ionophore X537A. J Cell. Biol. 66(2):425-443.
   Chacko S., Conti, MA, and Adelstein, RS. (1977). The effect of phosphorylation of smooth muscle myosin on actin activation and Ca2+ regulation. Proc. Natl. Acad. Sci. (USA). 74:129-133.
   Chacko, S. (1981) Effect of phosphorylation Ca2+ and tropomyosin on actin-activated ATPase activity of mammalian smooth muscle myosin. Biochemistry. 20:702-703.
   Chacko, S. and Rosenfeld, A. (1982) Regulation of actin-activated hydrolysis by arterial myosin. Proc. Natl. Acad. Sci. (USA) 79:292-296.
   Miyata, H. and Chacko, S. (1986) Role of tropomyosin in smooth muscle contraction: The effect of tropomyosin binding to actin on actin-activation of myosin ATPase. Biochemistry. 25:2725-2729.
   Horiuchi, KY., and Chacko, S. (1989) Caldesmon Inhibits the cooperative turning-on of the smooth muscle heavy meromyosin by tropomyosin-actin. Biochemistry,28:9111-911
   Chacko, S. and Eisenberg, E. (1990). Cooperativity of gizzard acto-HMM ATPase in the presence of gizzard tropomyosin. J. Biol.Chem.265:2105-2110.
   Samuel, M., Chowrashi, PK., Pepe, FA., and Chacko, S. (1990) Effects of phosphorylation, magnesium, and filament assembly on actin-activated ATPase of pig urinary bladder myosin. Biochemistry 29:7124-3132.
   Horiuchi, KY., Samuel, M., and Chacko, S. (1991) Mechanism for inhibition of acto-HMM ATPase by the actin/ calmodulin binding domain of caldesmon. Biochemistry 30:712-717.
   Horiuchi, KY., and Chacko, S. (1991) The mechanism for the inhibition of actin-activated ATPase of smooth heavy meromyosin by calponin. Biochem. Biophys. Res. Commun. 176:1487-1493.
   Chacko, S., Jacob, S., Horiuchi, K. (1994) Myosin I from mammalian smooth muscle is regulated by caldesmon-calmodulin. J. Biol. Chem. 269:1583-15807.
   Wang, Z., Horiuchi, KY., Jacob, SJ., Gopalakurup, SK, and Chacko, S. (1994) Overexpression, purification, and characterization of full-length and mutant caldesmon using a baculovirus expression system. J. Musc. Res. & Cell Motil. 15: 646-658.
   Horiuchi, KY. and Chacko, S. (1995) Effect of unphosphorylated smooth muscle on caldesmon-mediated regulation of actin filament velocity. J. Musc. Res. & Cell Motil. 16:11-19.
   Horiuchi, KY., Wang, Z., and Chacko, S. (1995) Inhibition of smooth muscle actomyosin ATPase by caldesmon is associated with caldesmon-induced conformational changes in tropomyosin bound to actin. Biochemistry.34: 16815.
   Wang, Z. , Horiuchi, KY., and Chacko, S. (1996) Characterization of the functional domains of the C-terminal region of caldesmon using full-length and mutant caldesmon molecules. J. Biol. Chem. 271:271:2234-2242.
   Wang, Z. and Chacko, S. (1996) Mutagenesis analysis of functionally important domains within the C-terminal end of smooth muscle caldesmon. J. Biol. Chem. 27:25707-25714.
   DiSanto, ME., Cox, RH., Wang, Z., and Chacko, S. (1997) Increased expression of myosin II with insertion in the NH2-terminal region of the distributing (muscular) arteries. Amer. J.Physiol. 272(Cell) C1532-C1542.
   Wang, Z., Yang, Z-Q., and Chacko, S. (1997) Functional and structural relationship between the calmodulin-binding, actin-binding, and actomyosin-ATPase inhibitory domains on the C terminus of smooth muscle caldesmon .J. Biol. Chem.272: 16896-16903.
   Chacko, S., DiSanto, M., Wang, Z, Zderic, SA., and Wein, AJ. (1997).Contractile protein changes in urinary bladder smooth muscle during obstruction-induced hypertrophy. Scand. J.Urol. Neprol. 184: 67-76.
   Wang, Z., He, J., Yang, Z-Q., and Chacko, S. (1997) Both N-terminal myosin binding and C-terminal actin-binding sites on smooth muscle caldesmon are required for caldesmon-mediated inhibition of actin filament velocity. Proc. Natl Acad. Sci. 94: 11899-11904.
   Menon, C., and Chacko, S. (1998) Expression of caldesmon during differentiation of smooth muscle in the chicken gizzard. Tissue & Cell Res. 30:118-126
   DiSanto, M., Chacko, T., Hypolite, J., Broderick, G., Wein, AJ, and Chacko, S. (1998) Molecular Basis of Erecetile Function: Expression of myosin isoforms in smooth muscle cells in corpus cavernosum penis. Am. J. Physiology (Cell Physiol 44) 275:C976-C987.
   Gomes, CM., DiSanto, ME., Horan, P., Levine, RM., Wein, AJ., and Chacko, S. (2000) Improved contractility obstructed bladders after tadenan treatment is associated with reversal of altered myosin isoform expression. J. Urol. 163: 2008-2013.
   Hypolite, J., DiSanto, M., Zheng, Y., Chang, S., Wein, A., and Chacko, S. (2001) Regional variation on myosin isoforms and phosphorylation at the resting tone in urinary bladder smooth muscle. Am. J. Physiol.(Cell) 280: C254-C264
   Sanchez-Ortiz, R., Wang, Z., Menon, C., DiSanto, ME., Wein, AJ, and Chacko, S. (2001). Estrogen modulates the expression of myosin heavy chain in detrusor smooth muscle. Am. J. Physiol. (Cell) 280: C433-C440.
   Arafat, HA., Kim, G., DiSanto, ME., Wein, AJ, and Chacko, S. (2001) Heterogeneity of bladder myocytes in vitro: modulation of myosin isoform expression. Tissue & Cell. 33 (3) 1-14.
   Chang, S., Hypolite, J., Zderic, SA., Wein, AJ., Chacko, S. DiSanto, ME (2002) Enhanced force generation by corpus cavernosum smooth muscle in rabbits with partial bladder outlet obstruction. J. Urol 167:2636-2644
   Zheng, Y., Weber, W.T., Wang, S., Wein, A.J., Chacko, S., and DiSanto, M.E. (2002) Establishment of a phenotypically stable bladder myocyte cell line from hypertrophied detrusor smooth muscle. Am. J. Physiol Cell Physiology 283:C373-382
   DiSanto ME, Stein R, Chang S, Hypolite JA, Zheng Y, Zderic S, Wein AJ, Chacko S. (2003) Alteration in the expression of myosin isoforms in detrusor smooth muscle following bladder outlet obstruction. Am J Physiol Cell Physiol., 285(6):C1397-410.
   Bing W, Chang S, Hypolite JA, DiSanto ME, Zderic SA, Rolf L, Wein AJ, Chacko S. (2003) Obstruction-induced changes in urinary bladder smooth muscle contractility: A role for Rho-kinase. Am J Physiol Renal Physiol., ;285(5):F990-7.
   Zhang E, Stein R, Chang S, Zheng Y, Zderic SA, Wein AJ, and Chacko S. (2004) Smooth Muscle Hypertrophy following Partial Bladder Outlet Obstruction is Associated with Overexpression of Non-Muscle Caldesmon. Am J. Pathology.,164: 601-612.
   Austin JC;Chacko SK;DiSanto M;Canning DA;Zderic SA; (2004) A male murine model of partial bladder outlet obstruction reveals changes in detrusor morphology, contractility and Myosin isoform expression Journal of Urology 172(0): 1524-1528
   Su X;Changolkar A;Chacko S;Moreland RS; (2004) Diabetes decreases rabbit bladder smooth muscle contraction while increasing levels of myosin light chain phosphorylation Am J Physiol Renal Physiol 287(4): F690-9
   Chang S;Hypolite JA;Velez M;Changolkar A;Wein AJ;Chacko S;DiSanto ME; (2004) Downregulation of cGMP-dependent protein kinase-1 activity in the corpus cavernosum smooth muscle of diabetic rabbits Am J Physiol Regul Integr Comp Physiol 287(4): R950-60.
   Chacko S.;Chang S;Hypolite J;DiSanto ME;Wein AJ; (2004) Alteration of Contractile and Regulatory Proteins Following Partial Bladder Outlet Obstruction. Scandinavian Journal of Urology & Nephrology, 215:26-36
   Chang S, Hypolite JA, Wein AJ, Chacko S, Disanto ME (2005) Increased corpus cavernosum smooth muscle tone associated with partial bladder outlet obstruction is mediated via Rho-kinase. Am J Physiol Regul Integr Comp Physiol.;289(4):R1124-30.
   Changolkar A;Hypolite J;DiSanto ME;Oates P;Wein AJ;Chacko S; (2005) Diabetes-Induced Decrease in Detrusor Smooth Muscle Force is Associated with Oxidative Stress and Overactivity of Aldose Reductase. Journal of Urology 173:309-313
   Mannukarottu, AS., Hypolite, JA., Zderic. SA., Wein, AJ., Chacko, S., DiSanto, ME. (2005) Regional Alterations in the Expression of Smooth Muscle Myosin Isoforms in Response to Partial Bladder Outlet Obstruction. Journal of Urology 173:302-308
   Chang S, Hypolite JA, Disanto ME, Changolkar A, Wein AJ, Chacko S (2005) Increased basal phosphorylation of detrusor smooth muscle myosin in Alloxan-induced diabetic rabbit is mediated by up-regulation of Rho-kinase and CPI-17. Am J Physiol Renal Physiol. 2005 Oct 4
   Mannukarottu, AS., DiSanto, ME., Zderic. SA., Wein, AJ., Chacko, S (2005) Altered expression of thin
   filament-associated proteins in hypertrophied urinary bladder smooth muscle. Neurourol Urodyn. 25(1):78-88
   Mannukarottu, AS., DiSanto, ME., Zderic, SA., Wein, AJ., Chacko, S (2006)Altered expression of thin filament-associated proteins in hypertrophied urinary bladder smooth muscle. Neurourol Urodyn. 25(1):78-88.
   Hypolite JA, Chang S, Zheng Y, DiSanto ME, Zderic SA, Wein AJ, Chacko S (2006) Partial bladder outlet obstruction induces urethral smooth muscle hypertrophy and decreased force generation. J Urol. 175(2):777-82.
   Macarak, EJ., Schultz, J., Zderic, SA., Sado, Y., Polyak, E., Chacko, S, and Howard, PS. (2006) Smooth muscle trans-membrane sarcoglycan complex in partial bleadder ouitlet obstruction. Histochemistry. Cell Biol. 2006 Jan 25;:1-12.
   LaBelle E., Zderic, SA., Delaney, D., Hypolyte, J., Wein, A.J. and Chacko, S. (2006)Lipid signaling changes in smooth muscle remodeling associated with partial urinary bladder outlet obstruction. Neurourol Urodyn.;25(2):179-84.
   Basha, M., Chang, S., Somolock, E.M., Moreland, R.S., Wein, A.J., and Chacko S. (2006) Regional differences in myosin heavy chain isoform expression and maximal shortening velocity of rat vaginal wall smooth muscle. Am. J. Physiol. Regul Integr. Comp. Physiol 291(4):R1076-84.
   Clement, MR, Austin, JC, Delaney, DJ , Sliwoski, J., Hill, GC.Canning, DA, DiSanto, ME, Chacko, S., Zderic S. (2006) Activation of the calcineurin pathway is associated with detrusor decompensation: a potential therapeutic target. J Urol. 2006 Sep;176(3):1225-9.
   Stanton, M., Austin, JC, Delaney, DJ.,Gosfield A, J. Marx, J, Zderic, S, Chacko, S. &. Moreland R (2006)
   Partial Bladder Outlet Obstruction Selectively Abolishes Protein Kinase C Induced Contraction of Rabbit Detrusor Smooth Muscle. J Urol. Volume 176, Pages 2716-2721
   Deng, M., Mohanan, S., Polyak E., and Chacko S. (2007) Caldesmon is necessary for maintaining the actin and intermediate filaments in cultured bladder smooth muscle cells. Cell Motility and the Cytoskeleton 64:951-965
3. Research Support
   Ongoing Research Support

1. NIH P50 DK52620 (PI: Chacko, Samuel K.) - 9/1/2003 - 8/31/2013
   Remodeling of Bladder Smooth Muscle in Outlet Obstruction- The goal of the Urology Research Center in the Division of Urology at the University of Pennsylvania is to elucidate molecular mechanisms for smooth muscle dysfunction in outlet obstruction. There are three projects and two cores in the Center. The projects are (1) Extracellular Matrix Changes in Response to Obstruction- PI, Macarak (2) Effect of Extracellular Matrix and Stretch on the Expression of Smooth Muscle Phenotype During Detrusor Smooth Muscle Remodeling- PI, DiSanto; (3) Cellular and Molecular Basis of Detrusor Contractility and Bladder Dysfunction in Obstruction-Induced Detrusor Remodeling- PI, Chacko; Core A (Administrative Core) - PIs Chacko and Wein; Core B: Bladder Tissue Core, PI - Zderic; Pilot & Feasibility 1) N-cadherin-mediated adhesion during bladder outlet obstruction- PI., Glenn Radice; Pilot & Feasibility 2) Interrelationships between urodynamics and arousal, PI – Rita Valentino
   Role: PI
   Overlap: None
2. NIH DK-069898 (PI: Chacko, Samuel K.)- 02/01/2004- 01/31/2009
   Disruption of Caldesmon Gene Expression in Bladder Myocyte- The goal of this proposal is to develop and characterize two tools to study the physiological function for caldesmon (CaD), an actin/calmodulin-binding protein associated with smooth muscle thin filaments and thought to play a role in the maintenance of smooth muscle contractile apparatus and the regulation of contraction. These tools are 1) a knockout (KO) mouse model with disruption of the gene that encodes CaD and 2) a rabbit bladder smooth muscle cell line (BSM) which maintains the smooth muscle phenotype, including the ability to contract in response to agonists. We have been successful in making a CaD mouse KO model by homologous recombination.
   Role: PI
   Overlap: None
3. NIH T32-DK-07708 (PI: Wein, Alan J.) 09/30/2003-9/29/2008
   Physician and Scientist Training in Urological Research- The goal of T32 training program is to train Ph.D. degree holders in basic urologic research.
   Role: Co-PI
   Overlap: None
   Completed Research Support
4. NIH RO1 DK55042 09/30/1998-08/31/2003
   Mechanisms for alerted detrusor contractility in diabetes- The objective of this proposal was to elucidate the biochemical and molecular mechanism for alterations in the contractility of detrusor smooth muscle.
   Overlap: The present proposal is an extension of this study as well as new approach to study the role of oxidative stress in the diabetes-induced urologic complications.
5. NIH RO1 DK57252 05/01/99-01/31/02
   Obstruction-induced changes in bladder muscle- The objective of this proposal is to test the hypothesis that the depressed function of obstructed bladders is the result of alterations in both excitation contraction-coupling and the contractile apparatus in the detrusor smooth muscle.
   Overlap: None