Integrative Medical Sciences
Charles K. Thodeti, Ph.D.
Assistant Professor of Vascular Biology
Department of Integrative Medical Sciences
College of Medicine
Ph.D., Zoology (Physiology and Biochemistry Concentration), S. V. University, Tirupati, India - 1994
M.S., Zoology (Reproductive Physiology Specialization), S. V. University, Tirupati, India - 1987
B.S., Botany/Chemistry majors, S. V. University, Tirupati, India - 1985
Assistant Professor of Vascular Biology, Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio - 2009-Present
Instructor/Staff Scientist, Harvard Medical School/Children's Hospital, Boston, Mass. - 2004-2009
Research Associate Professor, University of Copenhagen, Denmark - 2000-2004
Post-Doctoral Fellow, Lund University, Sweden - 1997-2000
Research Associate, University of Hyderabad, Hyderabad, India - 1995-1996
Mechanical Control of Endothelial Cell Function, Angiogenesis and Stem Cell Differentiation
Cells within all living tissues encounter mechanical forces continuously within a changing dynamic environment, and increasing evidence suggests that mechanical forces regulate cell growth, differentiation, motility, protein synthesis and gene expression. Importantly, mechanical forces are critical regulators of cardiovascular physiology and pathophysiology. Therefore, understanding how cells sense and convert mechanical signals into biochemical signals, mechanotransduction, could offer novel therapeutic targets for treatment of various cardiovascular diseases and in vitro engineering of organs and tissues such as blood vessels. The long-term goal of my research is to work at the interface between soluble and solid state biochemistry using multidisciplinary approaches to investigate the biophysical, biomechanical and biomechanical mechanisms regulating endothelial cell function and angiogenesis and utilize the knowledge to develop effective vascular normalization therapies for cardiovascular abnormalities such as atherosclerosis, hypertension, diabetes and cancer.
Currently, my laboratory is focused on understanding the role of mechanosensitive TRPV4 ion channels in the regulation of:
- Tumor angiogenesis: Tumor vessels are characterized by abnormal morphology and patterning that cause vascular hyperpermeability and inefficient delivery of anti-cancer agents. We recently demonstrated that these vessel malformations may arise from aberrant Rho-mediated mechanosensing exhibited by tumor endothelial cells in response to mechanical strain. We also found that TRPV4 channels are required for endothelial cell reorientation in response to mechanical force. Therefore, we are investigating the role of TRPV4 channels and dependent signaling mechanisms in the regulation of tumor endothelial cell mechanosensitivity in order to identify novel targets that can be potentially used to normalize abnormal tumor vasculature and improve delivery of chemotherapeutic drugs in vivo.
- Stem cell differentiation into bone and cartilage: Mechanical forces are critical determinants of tissue morphogenesis including bone which is continuously exposed to mechanical forces. Indeed, local micromechanical forces have been shown to regulate human mesenchymal stem cell commitment to bone forming osteoblast like cells. Our focus in this project is to elucidate the biomechanical mechanisms that regulate stem cell differentiation in to bone and cartilage. To this end, we are collaborating with the Departments of Polymer Engineering, University of Akron and Plastic Surgery, Akron Children's Hospital to develop tissue engineering scaffolds that are mechanically osteo-inductive for bone regeneration therapy.
Jones TJ, Adapala RK, Geldenhuys WJ, Bursley C, Aboualaiwi WA, Nauli SM, Thodeti CK. Primary cilia regulates the directional migration and barrier integrity of endothelial cells through the modulation of hsp27 dependent actin cytoskeletal organization. J Cell Physiol. 2011 Feb 24. doi: 10.1002/jcp.22704. [Epub ahead of print]
Ohanyan VA, Guarini G, Thodeti CK, Talasila PK, Raman P, Haney RM, Meszaros JG, Damron DS, Bratz IN. Endothelin-mediated in vivo pressor responses following TRPV1 activation. Am J Physiol Heart Circ Physiol. 2011 Sep;301(3):H1135-42. Epub 2011 Jun 24.
Adapala RK, Talasila PK, Bratz IN, Zhang DX, Suzuki M, Meszaros JG, Thodeti CK. PKCα mediates acetylcholine-induced activation of TRPV4-dependent calcium influx in endothelial cells. Am J Physiol Heart Circ Physiol. 2011 Sep;301(3):H757-65. Epub 2011 Jun 24.
Matthews BD, Thodeti CK, Tytell JD, Mammoto A, Overby DR, Ingber DE. Ultra-rapid activation of TRPV4 ion channels by mechanical forces applied to cell surface beta1 integrins. Integr Biol (Camb). 2010 Sep;2(9):435-42. Epub 2010 Aug 20.
Chancellor TJ, Lee J, Thodeti CK, Lele T. Actomyosin tension exerted on the nucleus through nesprin-1 connections influences endothelial cell adhesion, migration, and cyclic strain-induced reorientation. Biophys J. 2010 Jul 7;99(1):115-23. Erratum in: Biophys J. 2010 Aug 9;99(4):1329.
Thodeti, C.K., Matthews, B., Ravi, A., Mamotto, A., Ghosh, K., and Bracha, A., Ingber, D.E. (2009) TRPV4 channels mediate cyclic strain-induced endothelial cell reorientation through integrin to integrin signaling. Circ. Res. 104:1123-1130.
Alenghat, F.J., Tytell, J., Thodeti, C.K., Derrien, A., and Ingber, D.E. (2009) Mechanical control of cAMP signaling through integrin-dependent activation of heterotrimeric Gαs protein in focal adhesions. J. Cell. Biochem. 106:529-38.
Ghosh, K., Thodeti, C.K., Dudley, A.C., Mammoto, A., Klagsbrun, M., and Ingber, D.E. ( 2008) Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro. Proc. Natl. Acad. Sci. USA 105: 11305-10.
Lele, T*., Thodeti, C.K*., Pendse, J., and Ingber, D.E. (2008) Investigating complexity of protein-protein interactions in focal adhesions. Biochem. Biophys. Res. Commun. 369:929-34
*Shared first author.
Xia, N., Thodeti, C.K., Hunt, T.P., Xu, Q., Ho, M., Whitesides, G.M., Westervelt, R., and Ingber, D.E (2008) Directional control of cell motility through focal adhesion positioning and spatial control of Rac activation. FASEB J. 22: 1649-59.
Lele, T., Thodeti, C.K., and Ingber, D.E. (2006) Force meets chemistry: analysis of mechanochemical conversion in focal adhesions using fluorescence recovery after photobleaching. J.Cell.Biochem. 97:1175-83. (Cover Page).
Thodeti, C.K., Frohlich, C., Nielsen, C.K., Takada, Y., Fassler, R., Albrechtsen, R. and Wewer, U.M. (2005) ADAM12-mediated focal adhesion formation is differently regulated by β1 and β3 integrins. FEBS Lett. 579: 5589-95.
Thodeti, C.K., Frohlich, C., Nielsen, C.K., Holck, P., Sundberg, C., Kveiborg, M., Mahalingam, Y., Albrechtsen, R., Couchman, J.R. and Wewer, U.M. (2005) Hierarchy of ADAM12 binding to integrins in tumor cells. Exp Cell Res. 309:438-50.
Sundberg, C*., Thodeti, C.K*., Kvieborg, M., Larsson, C., Parker, P., Albrechtsen, R., and Wewer, U,M. (2004) Regulation of ADAM12 cell-surface expression by protein kinase C epsilon. J. Biol.Chem. 279:51601-11.
*Shared first author
Thodeti, C.K., Albrechtsen, R., Grauslund, M., Asmar, M., Larsson, C., Takada, Y., Mercurio, A., Couchman, J.R., and Wewer, U.M. (2003) ADAM12/syndecan-4 signaling promotes β1integrin-dependent cell spreading through PKCα and Rho. J. Biol.Chem. 278:9576-9584.
Kawaguchi, N., Sundberg, C., Kveiborg, M., Moghadaszadeh, B., Asmar, M., Dietrich N., Thodeti C.K, Nielsen, F.C., Moller, P., Mercurio, A.M., Albrechtsen, R., and Wewer,U.M.(2003) ADAM12 induces actin cytoskeleton and extracellular matrix reorganization during early adipocyte differentiation by regulating beta1 integrin function. J.Cell Sci. 116: 3893-904.
Thodeti, C.K., R. Massoumi ., L. Bindslev., and A. Sjolander. (2002) Leukotriene D4 induces association of active RhoA with phospholipase C-g1 in intestinal epithelial cells. Biochem. J. 365:157-163.
Thodeti, C.K., and Sjölander, A. (2002) Leukotriene D4-induced calcium signalling in human intestinal epithelial cells. Adv. Exp. Med. Biol. 507: 187-191.
Thodeti, C.K., Nielsen, C.K., Larsson, C., and Sjölander, A. (2001) The epsilon isoform of protein kinase C is involved in the regulation of the LTD4-induced calcium signal in human intestinal epithelial cells. Exp.Cell.Res. 262: 95-103.
Thodeti , C.K., Adolfsson, J., Juhas, M., and Sjölander, A. (2000) Leukotriene D4 triggers an association between Gβγ subunits and phospholipase C-γ1 in intestinal epithelial cells. J.Biol.Chem. 275: 9849-9853.
Srinivasa Reddy., P., Charles Kumar, T., Narasa Reddy, M., Sarada, Ch., and Reddanna, P. (2000) Differential formation of octadecadienoic acid and octadecatrienoic acid products in control and injured/infected potato tubers. Biochim. Biophys.Acta 1483: 294-300.
Anuradha D., Reddy K.V., Charles Kumar, T., Neeraja S., Reddy P.R., and Reddanna P. (2000) Purification and characterization of rat testicular glutathione S-transferases: role in the synthesis of eicosanoids. Asian J.Androl. 2 :277-82.