Musculoskeletal Diseases


 

T. Michael Underhill, Ph.D.
Professor, Cellular & Physiological Sciences

604-822-5833
tunderhi@brc.ubc.ca


Research Summary

Dr. Underhill’s research interests involve understanding how changes at themolecular level influence cell fate decisions and the subsequent series of events that are involved in establishment of a skeleton. The initial focus of his research was on understanding the importance of retinoic acid receptor-mediated signaling in chondrogenesis. Its scope has now broadened to include analysis of numerous factors in skeletal development. These studies involve extensive use of microarray-based strategies coupled with functioning profiling to delineate the genetic programs underlying chondrogenesis. Similar strategies are also being employed to identify the transcriptional networks operating within the osteogenic program. Knowledge gained from these studies will determine the molecular basis of human congenital skeletal defects and potentially lead to novel therapeutic avenues to promote bone and cartilage formation for the treatment of skeletal diseases such as arthritis and osteoporosis.


Selected Publications

Ye, M., Berry, K.M., Asai-Coakwell, M., Sundaresan, P., Footz, T., French, C.R., Abitbol, M., Fleisch, V.C., Corbett, N. Allison, W.T., Drummond, G., Walter, M.A., Underhill, T.M., Waskiewicz, A.J. and Lehmann, O.J. (2010) Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies. Human Molecular Genetics 19:287-298

James, C.G., Stanton, L.A., Agoston, H., Ulici, V., Underhill, T.M. and Beier, F. (2010) Genome-wide analyses of gene expression during mouse endochondral ossification. PLoS One 13;5:e8693

Shankar, J., Messenberg, A., Chan, J., Underhill, T.M., Foster, L.J., and Nabi, I.R. (2010) Pseudopodial actin dynamics control epithelia-mesenchymal transition in metastatic cancer cells. Cancer Research 70:3780-90

Karamboulas, K., Dranse, H. and Underhill, T.M. Regulation of BMP-dependent chondrogenesis in early limb mesenchyme by TGFb signals. (J. Cell Science, in press)

Su, L., Cheng, H., Sampaio, A.V., Nielsen, T.O. and Underhill, T.M. EGR1 reactivation by histone deacetylase inhibitors promotes synovial sarcoma cell death through the PTEN tumor suppressor. (Oncogene, in press).

Weston, A.D., Rosen, V., Chandraratnas, R.A.S. and Underhill, T.M. (2000) Regulation of skeletal progenitor differentiation by the BMP and retinoid signaling pathways. Journal of Cell Biology, 148:601-612.

Weston, A.D., Chandraratna, R.A.S., Torchia, J. and Underhill T.M. (2002) Requirement for RAR-mediated gene repression in skeletal progenitor differentiation. Journal of Cell Biology 158(1): 39-51.

Weston, A.D., Sampaio, A.V., Ridgeway, A.G., and Underhill, T.M. (2003) Inhibition of p38 MAPK signaling promotes muscle formation. Journal of Cell Science, 166:2885-93.

Weston, A.D., Blumberg, B., and Underhill, T.M. (2003) Active repression by unliganded retinoid receptors in development: less is sometimes more. Journal of Cell Biology, 161:233-8.

Brown, K., Chen, Y., Underhill T.M., Mymyrk, J.S., Torchia, J. (2003) The coactivator p/CIP/SRC-3 facilitates retinoic acid receptor signalling via recruitment of GCN5. Journal of Biological Chemistry, 278(41):39402-12.

Wongtrakool, C., Malpel, S., Gorenstein, J., Sedita, J., Ramirez, M.I., Underhill, T.M., Cardoso, W.V. (2003) Downregulation of RARα is required for sacculation and type I cell formation in the developing lung. Journal of Biological Chemistry, 278(47):46911-8.

Jay, K.E., Rouleau, A., Underhill, T.M. and Bhatia, M. (2004) Identification of a novel population of primitive human cord blood cells with hematopoieticytic and chondrocytic potential Cell Research, 14:268-82.

Hoffman, L.M., Garcha, K., Karamboulas, K., Cowan, M.F. , Drysdale, L.M.Horton, W.A and Underhill, T.M.* (2006) BMP action in skeletogenesis involves attenuation of retinoid signaling. Journal of Cell Biology 174(1):101-13.

Luciani, D.S., Yang, T., Bychkivska, Y., Frey, M.H.Z., Jeffrey, K.D., Kalynyak, T.B., Sampaio, A.V., Underhill, T.M. and Johnson, J.D. (2009) Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and β-cell death. Diabetes58:422-32

Asai-Coakwell, M., French, C.R., Ye, M., Garcha, K., Bigot, K., Perera, A.G., Staehling-Hampton, K., Mema, S.C., Chanda, B., Mushegian, A., Bamforth, S., Doschak, M.R., Li, G., Dobbs, M.B., Giampietro, P.F., Brooks, B.P., Vijayalakshmi, P., Sauvé, Y., Abitbol, M., Sundaresan, P., Heyningen, V.V., Pourquié, O., Underhill, T.M., Waskiewicz, A.J., Lehmann, O.J. (2009) Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes. Hum. Mol. Genet. 18(6):1110-21

Welch, I., Cowan, M., Beier, F. and Underhill, T.M.* (2009) The retinoic acid binding protein Crabp2 is increased in murine models of degenerative joint disease. Arthritis Res. Ther. 11(1):R14

Umoh, J.U., Sampaio, A.V., Welch, I., Pitelka, V., Goldberg, H.A., Underhill, T.M., and Holdsworth, D.W. (2009) In vivo micro-CT analysis of bone remodeling in a rat calvarial
defect model. (Phys. Med. Biol., in press).

Widenmaier, S.B., Sampaio, A.V., Underhill, T.M., McIntosh, C.H. (2009) Non-canonical activation of Akt/PKB in beta -cells by the incretin hormone glucose-dependent insulinotropic polypeptide (GIP). J. Biol. Chem. (in press)


Lab Members

Martin Arostegui, Graduate Research Assistant
Wilder Scott, Graduate Research Assistant
Daniel Tausan, Laboratory Assistant
Kimberly Wiegand, Postdoctoral Fellow
Ryan Vander Werff, Research Assistant