Chaur-Dong Hsu, MD, MPH, FACOG
Fredrick Pavalko, PhD
Professor
  • Department of Cellular & Integrative Physiology
    Indiana University School of Medicine
    Indianapolis, Indiana, USA
    Phone: 317-274-3140
    E-mail: fpavalko@iupui.edu

Education

  • 1982, B.S. in Biology, Guilford College, Greensboro, North Carolina
  • 1987, Ph.D. in Cell Biology, Florida State University, Tallahassee, Florida
  • 1987-1991, Postdoctoral Fellowship, Cell Biology and Anatomy, University of North Carolina at Chapel Hill, NC

 

Biography

The primary focus of my laboratory’s research is in understanding the cellular mechanisms of mechanotransduction through integrins in osteoblasts, osteocytes and endothelial cells. Understanding fundamental biology of signal transduction in bone and vascular tissues in response to mechanical cues from the microenvironment is important to a more complete understanding of how best to treat disease. We have developed the novel concept of the “mechanosome” to experimentally test how cells detect and respond appropriately to the mechanical loading environment that exists in the skeleton. My laboratory has over 15 years of experience using in vitro application of mechanical stimuli to cells to evaluating the cellular mechanisms of mechanotransduction. Typically studies on mechanotransduction have focused primarily on understanding the signaling pathways that stimulate cellular responses to load. Recently we have taken a different approach by also trying to understand and alter the structural, signaling and transcriptional molecules that suppress the stimulatory effects of loading.  Manipulating these “off switches” might be of much greater therapeutic utility than intensifying the “on switches.”  We propose that distinct types of mechanical loading such as fluid shear stress or substrate strain can be manipulated, so that modest mechanical loading can have sustained and/or enhanced anabolic effects via suppressing the MTD “off switches.”  We have studied the roles of integrin-associated tyrosine kinases including FAK, Pyk2 and Src which are hot spots for mechanical sensing in focal adhesions. We are working to test the role of Src kinase in osteocytes during mechanotransduction in bone. We are using in vivo and in vitro models to test the novel hypothesis that Src functions in osteocytes to suppress load-induced bone formation. We predict that targeting osteocytes for deletion of Src kinase with remove a negative regulator of bone formation resulting in increased basal and load-induced bone density and that it accomplishes this, in part, by epigenetic regulation of critical bone genes including SOST, RANKL and OPG.

Research Interest

Bone cell mechanotransduction. Mechanical signaling through focal adhesions. Bone and endothelial cell biology, apoptosis, focal adhesions, cell adhesion molecules, cytoskeleton, mechanotransduction, prostaglandin metabolism, cell motility and regulation of contractility, cytoskeletal-membrane interactions.

 

Scientific Activities:

Honors, Awards and Professional Societies
  • Elwert Award in Medicine, IUSM 2016
  • Trustee Teaching Award, Indiana University, 2001
  • Young Investigator Award, Fluid Flow in Bone Workshop, 2001
  • NIH Shannon Award, 1994-1996
  • NIH National Research Service Award, 1988-1991.
  • Sigma Xi Pre-doctoral Grant-in-Aid, 1985
  • American Physiological Society
  • American Society for Cell Biology
  • American Society for Bone and Mineral Research
  • Sigma Xi Scientific Research Society
  • Society for Physical Regulation in Biology and Medicine

 

Publications

  1. Ward, S., Roberts, T.M., Strome, S., Pavalko F.M. and Hogan, E. (1986) Monoclonal antibodies that recognize a polypeptide antigenic determinant shared by multiple Caenorhabditis elegans sperm-specific proteins. Journal of Cell Biology 102: 1778-1786.
  2. Roberts, T.M., Pavalko, F.M. and Ward, S. (1986) Membrane and cytoplasmic proteins are transported in the same organelle complex during nematode spermatogenesis. Journal of Cell Biology 102: 1787-1796.
  3. Pavalko, F.M. and Roberts, T.M. (1987) Caenorhabditis elegans spermatozoa assemble membrane proteins onto the surface at the tips of pseudopodial projections. Cell Motility and the Cytoskeleton 7:169-177.
  4. Pavalko, F.M., Holliday, L.S. and Roberts, T.M. (1988) Relationship between plasma membrane mobility and substrate attachment in the crawling movement of spermatozoa from Caenorhabditis elegans. Cell Motility and the Cytoskeleton 11:16-23.
  5. Pavalko, F.M. and Roberts, T.M. (1989) Posttranslational insertion of a membrane protein on Caenorhabditis elegans sperm occurs without de novo protein synthesis. Journal of Cellular Biochemistry 41:57-70.
  6. Turner, C.E., Pavalko, F.M. and Burridge, K. (1989) The role of phosphorylation and limited proteolytic cleavage of talin and vinculin in the disruption of focal adhesion integrity. Journal of Biological Chemistry 264:11938-11944.
  7. Pavalko, F.M., Otey, C.A. and Burridge, K. (1989) Identification of a filamin isoform enriched at the ends of stress fibers in chick embryo fibroblasts. Journal of Cell Science 94:109-118.
  8. Pavalko, F.M., Turner, C.E. and Burridge, K. (1989) Regulation of Actin-membrane interactions at focal adhesions of cultured cells. In: Advances in Protein Phosphatases, J. Di Salvo and W. Merlevede, eds., Leuven Univ. Press, Leuven Belgium, 5:279-298.
  9. Otey, C.A., Pavalko, F.M. and Burridge, K. (1990) An interaction between α-actinin and the ß1 integrin subunit in vitro. Journal of Cell Biology 111:721-730.
  10. Burridge, K., Nuckolls, G., Otey, C.A., Pavalko, F.M., Simon, K. and Turner, C.E. (1990) Actin membrane interaction in focal adhesions. Cell Differentiation and Development 32:337-342.
  11. Pavalko, F.M., Otey, C.A., Simon, K.O. and Burridge, K. (1991) α-Actinin: a direct link between actin and integrins. Biochemical Society Transactions 19:1065-1069.
  12. Simon, K.O., Otey, C.A., Pavalko, F.M. and Burridge, K. (1991) Protein interactions linking actin to the plasma membrane in focal adhesions. Current Topics in Membranes. 38:57-64.
  13. Pavalko, F.M. and Burridge, K. (1991) Disruption of the actin cytoskeleton by microinjection of proteolytic fragments of α-actinin. Journal of Cell Biology 114:481-491.
  14. Pavalko, F.M. and LaRoche, S.M. (1993) Activation of human neutrophils induces an interaction between the integrin ß2 subunit (CD18) and the actin-binding protein α-actinin. Journal of Immunology 151:3795-3807.
  15. Pavalko, F.M. and Otey, C.A. (1994) Role of adhesion molecule cytoplasmic domains in mediating interactions with the cytoskeleton. Proceeding of the Society for Experimental Biology and Medicine 205:282-293.
  16. Pavalko, F.M., Adam, L., Wu, M.F., Walker, T.L. and Gunst, S.J. (1995) Phosphorylation of the dense plaque proteins talin and paxillin during tracheal smooth muscle contraction. American Journal of Physiology: Cell Physiology 268:C563-571.
  17. Pavalko, F.M., Schneider, G., Burridge, K. and Lim, S.S. (1995) Immunodetection of α-actinin in focal adhesions is limited by antibody inaccessibility. Experimental Cell Research 217:534-540.
  18. Pavalko, F.M., Walker, D.M., Graham, L., Goheen, M., Doerschuk, C., and Kansas, G.S. (1995) The cytoplasmic domain of L-selectin interacts with cytoskeletal proteins via α-actinin: receptor positioning in microvilli does not require cytoskeletal associations. Journal of Cell Biology 129:115-1164.
  19. Garcia, J.G.N., Pavalko, F.M., and Patterson, C.E. (1995) Vascular endothelial cell activation and permeability responses to thrombin. Blood Coagulation and Fibrinolysis 6:609-626.
  20. Pavalko, F.M. (1995) Cytoskeleton-plasma membrane interactions. In: Encyclopedia of Molecular Biology and Molecular Medicine, R.A. Myers, ed., VCH Publishers, Inc. New York, NY. 1: 451-460.
  21. Kansas, G.S. and Pavalko, F.M. (1996) The cytoplasmic domains of E- and P-selectin do not constitutively interact with α-actinin and are not essential for leukocyte adhesion. Journal of Immunology 157:321-325.
  22. Wang, Z., Pavalko, F.M. and Gunst, S.J. (1996) Tyrosine phosphorylation of the dense plaque protein paxillin is regulated during smooth muscle contraction. American Journal of Physiology: Cell Physiology 271:C1594-1602.
  23. Schaphorst, K.L., Pavalko, F.M., Patterson, C.E., and Garcia, J.G.N. (1997) Thrombin-mediated focal adhesion plaque reorganization in endothelium: role of protein phosphorylation. American Journal of Respiratory Cell and Molecular Biology 17:443-455.
  24. Sampath, R., Gallagher, P.J. and Pavalko, F.M. (1998) Cytoskeletal interactions with the leukocyte integrin β2 cytoplasmic tail: activation-dependent regulation of associations with talin and α-actinin. Journal of Biological Chemistry 273: 33588-33594.
  25. Pavalko, F.M., Chen, N.X., Turner, C.H., Burr, D.B., Atkinson, S., Hsieh, Y.-F., Qiu, J. and Duncan, R.L. (1998) Fluid shear-induced mechanical signaling in MC3T3-E1 osteoblasts requires cytoskeleton-integrin interactions. American Journal of Physiology: Cell Physiology 275:C1591-C1601.
  26. Turner, C.H. and Pavalko, F.M. (1998) Mechanotransduction and functional response of the skeleton to physical stress: The mechanisms and mechanics of bone adaptation. Journal of Orthopedic Science 3:346-355.
  27. Turner, C.H., Duncan, R.L. and Pavalko, F.M. (1998) Mechanotransduction: an inevitable process for skeletal maintenance. In: Novel Approaches to Treatment of Osteoporosis. Russel, Skerry and Kollenkirchen, (eds.). pp157-178.
  28. Hurley, J.H., Bloem, F.M. Pavalko, L.J., Liu, J., Tian, M, Simon, J.R., and Yu, L (1999) Structure-function studies of the eighth hydrophobic domain of a serotonin receptor. Journal of Neurochemistry 72:413-21.
  29. Chen, N.X., Ryder, K.D., Pavalko, F.M., Turner, C.H., Burr, D.B., Qiu, J. and Duncan, R.L. (2000) Ca2+ regulates fluid shear-induced cytoskeletal reorganization and gene expression in osteoblasts. American Journal of Physiology: Cell Physiology 278:C989-997.
  30. Knepler, J.L., Taher, L.N., Gupta, M.P., Patterson, C., Pavalko, F.M., Ober, M.D. and Hart, M.C. (2001) Peroxynitrite (ONOO-) causes endothelial cell monolayer barrier dysfunction. American Journal of Physiology: Cell Physiology 281: C1064-1075.
  31. Sawyer, S.J., Norvell, S.M., Ponik, S.M. and Pavalko, F.M. (2001) Regulation of PGE2 and PGI2 release from human umbilical vein endothelial cells by actin cytoskeleton. American Journal of Physiology: Cell Physiology 281: C1038-1045.
  32. Torrungruang, K., Shah, R., Alvarez, M., Bowen, D.K., Gerard, R., Pavalko, F.M., Elmendorf, J.S., Charoonpatrapong, K., Hock, J., Rhodes, S.J., and, Bidwell, J.P. (2002) Osteoblast Intracellular Localization of Nmp4 Proteins. Bone 30: 931-936.
  33. Pavalko, F.M., Gerard, R.L., Ponik, S.M., Gallagher, P.J., Jin, Y., and Norvell, S.M. (2002) Fluid shear stress inhibits TNF-α-induced apoptosis in osteoblasts: a role for shear stress-induced activation of PI3-kinase and inhibition of caspase-3. Journal of Cellular Physiology 194: 194-205.
  34. Pavalko, F.M., Norvell, S.M., Burr, D.B., Turner, C.H., Duncan, R.L. and Bidwell, J.P. (2003) A Model for Mechanotransduction in Bone Cells: The Load-Bearing Mechanosomes. Journal of Cellular Biochemistry 88:104-112.
  35. Chen, N.X., Geist, D.J., Genetos, D.C., Pavalko, F.M. and Duncan, R.L. (2003) Fluid shear-induced NFκB translocation in osteoblasts is mediated by intracellular calcium release. Bone 33:399-410.
  36. Woods, A.M., Rodenberg, E., Hiles, M. and Pavalko, F.M. (2004) Improved biocompatibility of small intestinal submucosa (SIS) following conditioning by human endothelial cells. Biomaterials, 25: 515-525.
  37. Norvell, S.M. Ponik, S.M., Bowen, D.K., Gerard, R. and Pavalko, F.M. (2004) Fluid shear stress induction of Cox-2 protein and prostaglandin release in cultured MC3T3-E1 osteoblasts does not require intact microfilaments or microtubules. Journal of Applied Physiology, 96:957-966.
  38. Ponik, S.M. and Pavalko, F.M. (2004) Formation of focal adhesions on fibronectin promotes fluid shear stress induction of COX-2 and PGE2 release in MC3T3-E1 osteoblasts. Journal of Applied Physiology, 97:135-142.
  39. Shah, R., Alvarez, M., Jones, D.R., Torrungruang, K., Watt, A.J., Selvamurugan, N., Partridge, N.C., Quinn, C.O., Pavalko, F.M., Rhodes, S.J. and Bidwell, J.P. (2004) Nmp4/CIZ regulation of matrix metalloproteinase 13 (MMP-13) response to parathyroid hormone in osteoblasts American Journal of Physiology: Endocrinology and Metabolism., 287:289-296.
  40. Norvell, S.M., Alvarez, M., Bidwell, J.P. and Pavalko, F.M. (2004) Fluid shear stress induces β-catenin signaling in osteoblasts. Calcified Tissue International, 75:396-404.
  41. Triplett, J.W., Herring, B.P. and Pavalko, F.M. (2005) Adenoviral transgene expression enhanced by co-treatment with etoposide in cultured cells. Biotechniques, 39:826-832.
  42. Charoonpatrapong, K., Shah, JR, Robling, A.G., Alvarez1, M., Clapp, D.W., Chen, S., Kopp, R.P, Pavalko, F.M., Yu, J., and Bidwell, J.P. (2006) HMGB1 expression and release by bone cells, Journal of Cellular Physiology, 207:480-490.
  43. Triplett, J.W. and Pavalko, F.M. (2006) Disruption of α-actinin-integrin interactions at focal adhesions renders osteoblasts susceptible to apoptosis. American Journal of Physiology: Cell Physiology, 291:909-921.
  44. Ponik, S.M., Triplett, J.W. and Pavalko, F.M. (2007) Osteoblasts and osteocytes respond differently to oscillatory and unidirectional fluid flow profiles. Journal of Cellular Biochemistry, 100:794-807.
  45. Triplett, J.W., Gerard-O’Riley, R., Tekulve, K., and Norvell, S.M., Pavalko, F.M. (2007) Mechanical stimulation by fluid shear stress enhances IGF-I receptor signaling in osteoblasts in a PKC-zeta-dependent manner. Molecular and Cellular Biomechanics, 4: 13-26.
  46. Panyayong, K., Shah, R, Yang, J., Alvarez, M., Pavalko, F.M., Gerard-O'Riley, R., Robling, A.G., Templeton, E., Bidwell, J.P. (2007) Nmp4/CIZ contributes to fluid shear stress induced MMP-13 gene induction in osteoblasts. Journal of Cellular Biochemistry, 102:1202-1213.
  47. Rodenberg, E. and Pavalko, F.M. (2007) Fibronectin type III connecting segment-derived peptides promote endothelial cell adhesion but not platelet adhesion: Implications in tissue engineering vascular grafts. Tissue Engineering, 13: 2653-2666.
  48. Pavalko, F.M. (2009) Cytoskeletal interactions with leukocyte and endothelial cell adhesion molecules. Current Topics in Membranes, 64: 133-156.
  49. Yang, Z., Bidwell, Young, S.R., Gerard-O’Riley, R., Wang, H. and Pavalko, F.M. (2010) Nmp4/CIZ
  50. inhibits mechanically-induced β-catenin signaling activity in osteoblasts. Journal of Cellular Physiology, 223: 435-441.
  51. Young, S.R.L., Gerard-O’Riley, R., Harrington, M. and Pavalko, F.M. (2010) Activation of NF-kB by fluid shear stress, but not TNF-α, requires focal adhesion kinase in osteoblasts. Bone. 47:74-82.
  52. Bidwell, J.P and Pavalko, F.M. (2010) Mechanosomes carry a loaded message. Science Signaling, 3,
  53. pe51.
  54. Bidwell, J.P. and Pavalko, F.M. (2010) The load-bearing mechanosome revisited. Clinical Reviews in Bone and Mineral Metabolism, 8:213-223.
  55. Wang, H., Young, S.R., O’Riley, R.L, Yang, Z., and Pavalko, F.M. (2011) Blockade of TNFR1 signaling: a role of oscillatory fluid shear stress in osteoblasts. Journal of Cellular Physiology, 226: 1044-1051.
  56. Young, S.R.L. and Pavalko, F.M. (2011) Cellular mechanisms of mechanotransduction in bone. In: A. Kamkin, I. Kiseleva (eds.), Mechanosensitivity and Mechanotransduction, Mechanosensitivity in Cells and Tissues 4: 277-296.
  57. Young, S.R.L., Hum, J., Rodenberg, E., Turner, C.H., and Pavalko, F.M. (2011) Non-overlapping functions for Pyk2 and FAK in osteoblasts during fluid shear stress-induced mechanotransduction. PLoS One, 6: e16026.
  58. Alvarez, M., Childress, P., Philip, B., Gerard-O'Riley, R., Hanlon, M., Herbert, B.S., Robling, A.G., Pavalko, F.M., and Bidwell, J.P. (2012) Generation and characterization of immortalized osteoblast cell lines generated from wild-type and Nmp4-null mouse bone marrow stromal cells using murine telomerase reverse transcriptase (mTERT). Journal of Cellular Physiology, 227:1873-82.
  59. Bidwell, J.P., Childress, P., Alvarez, M.B., Hood, M., He, Y., Pavalko, F.M., Kacena, M., and Yang, F.C. (2012) Nmp4/CIZ closes the parathyroid hormone (PTH) anabolic window. Crit. Rev. Euk. Gene Exp., 22:205-18.
  60. Hum, J.M., Siegel, A.P., Pavalko, F.M., and Day, R.N. (2012) Monitoring biosensor activity in living cells with fluorescence lifetime imaging microscopy. International Journal of Molecular Sciences, 13:14385-400.
  61. Cheng, Y.-H., Nguyen, K., O’Riley, R.L., Waning. D. L., Chitteti, B.R., Lin. H., Plett, A.P., Orschell, C.M., Srour, E.F., Mayo, L.D., Pavalko, F.M., and Bruzzaniti, A, Kacena, M.A. (2013) Pyk2 regulates megakaryocyte-induced increases in osteoblast number and bone formation. Journal of Bone and Mineral Research, 28: 1434-45.
  62. Castillo, A.B., Triplett J.W., Pavalko F.M. and Turner, C.H. (2014) Estrogen receptor-β regulates mechanical signaling in primary osteoblasts. American Journal of Physiology: Endocrinology and Metabolism, 306: 937-44.
  63. Hum J.M., Day R.N., Bidwell J.P., Wang Y., Pavalko F.M. (2014) Mechanical Loading in Osteocytes Induces Formation of a Src/Pyk2/MBD2 Complex That Suppresses Anabolic Gene Expression. PLoS ONE 9(5): e97942.
  64. Cheng, Y.-H., Streicher, D.A., Waning, D.L., Chitteti, B.R., Gerard-O’Riley, R., Horowitz, M.C., Bidwell, J.P., Pavalko, F.M., Srour, E.F., Mayo, L.D., Kacena, M.A. (2015) Signaling pathways involved in megakaryocyte-mediated proliferation of osteoblast lineage cells. Journal of Cellular Physiology, 230:578-586.
  65. Childress, P., Stayrook, K, Alvarez, M.B., Wang, Z., Shao, Y., Hernandez-Buquer, S., Mack, J.K., Grese, Z.R., He, Y., Horan, D., Pavalko, F.M., Warden, S.J., Robling, A.G., Yang, F.C., Allen, M. R., Krishnan, V., Liu, Y., Bidwell, J.P. (2015) Genome-wide mapping and interrogation of the Nmp4 anti-anabolic bone axis. Molecular Endocrinology. 29:1269-85.
  66. Wang, H., Liu, J.L., Yang, Y.J., , Cao, Q.W., Huo, X.P., Ma, S., Hu, J., Pavalko, F.M., Liu, Q.S. (2016) Hydroxy-Safflower Yellow A inhibits the TNFR1-mediated classical pathway by inducing shedding of TNFR1. Phytotherapy Research, 30:790-796.
  67. Bullock, W., Plotkin, L., Robling, A.G., Pavalko, F.M. Mechanotransduction in bone formation and maintenance. Metabolic Bone Diseases and Disorders of Mineral Metabolism, in press.

 

     
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