Matrix and Cell Biology in Skeletal Development: Molecular Mechanisms in Health and Disease
Dr Chan, Danny (陳振勝)
Associate Professor, Department of Biochemistry; Assistant Dean (Research Affairs), LKS Faculty of Medicine
BSc (Hon.), MSc, PhD (University of Melbourne)
- Email: firstname.lastname@example.org
- Tel: (852) 2819 9482; 2819 2818 (lab)
- Office: L3-67, Laboratory Block, 21 Sassoon Road, Hong Kong
My research interest is in skeletal biology, focusing on development, growth and degenerative processes of the skeleton in health and disease. The emphasis is on genes regulating the process of endochondral ossification. The approach is to identify novel disease genes and to model the disease in mice to define the precise molecular and developmental changes.
A major finding in our lab is the consequence of activating ER-stress signal in hypertrophic chondrocytes that induces a “reprogramming” event, and the cells become more “juvenile”. This was shown to be the molecular basis for metaphyseal chondrodysplasia type Schmid (MCDS), a human condition with disrupted endochondral ossification causing dwarfism. At present, we are focusing on defining the relationship between activation of ER-stress and the molecular changes that could induce chondrocyte reprogramming. Understanding this “reprogramming” progress not only has implications in the control of chondrocyte differentiation, but also regenerative strategies for degenerative cartilage diseases.
A related goal is to understand the signals controlling joint formation, with an emphasis in the formation of digit joints. More recently, we provided a mechanistic insight into how mutations in the IHH gene alter the signaling capacity and range of hedgehog proteins, as these mutations impair IHH interaction with partner molecules. The consequence is reduced digit outgrowth in development causing brachydactyly type A1 (BDA1). The impact of these mutations on hedgehog signal has broad implications as hedgehog proteins are involved in many development diseases and cancer biology.
I coordinate a Human Genetic Programme to identify genetic risk factors for intervertebral disc degeneration. Disc degeneration is a major cause of back pain. The aim is to understand the etiology of disc degeneration and a mean derive new strategies in the prevention and treatment of the disease.
An area of my expertise is extracellular matrix proteins. A new direction in my lab is to use the regenerative Planarian as a model organism to study the extracellular matrix niche of stem cell maintenance.
My Lab Group
Postgraduate Research Projects are Available in the Following Research Areas:
- Generation and analysis of mouse models with specific skeletal defects or intervertebral disc degeneration
- Molecular controls for skeletal patterning: Joint formation and digit patterning
- Role of cellular stress signals in cellular-decision making
- Extracellular matrix niche in stem cell maintenance and differentiation
Publications, Achievements, and Grants:
- Yang, L., Hui, W.S., Chan, W.C.W., Ng, V.C.W., Yam, T.H.Y., Leung, H.C.M., Huang, J-D, Shum, D.K.Y., Jie, Q., Cheung, K.M.C., Cheah, K.S.E., Luo, Z-J. and Chan, D. (2010) A splice-site mutation leads to haploinsufficiency of EXT2 mRNA for a dominant trait in a large family with multiple osteochondromas. J. Orthopad. Res. 28, 1522-1530
- Tsang, K. Y., Cheung, M. C., Chan, D., and Cheah, K. S. (2009) The developmental roles of the extracellular matrix: beyond structure to regulation, Cell Tissue Res. 339, 93-110
- Yang, F., Leung, V. Y., Luk, K. D., Chan, D., and Cheung, K. M. (2009) Mesenchymal stem cells arrest intervertebral disc degeneration through chondrocytic differentiation and stimulation of endogenous cells, Mol. Ther. 17, 1959-1966
- Gao, B., Hu, J., Stricker, S., Cheung, M., Ma, G., Law, K. F., Witte, F., Briscoe, J., Mundlos, S., He, L., Cheah, K. S., and Chan, D. (2009) A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range. Nature 458, 1196-1200
- Song, Y. Q., Cheung, K. M. C., Ho, D. W. H., Poon, S. C. S., Chiba, K., Kawaguchi, Y., Hirose, Y., Alini, M., Grad, S., Yee, A. F. Y. , Leong, J. C. Y., Luk, K. D. K., Yip, S. P., Karppinen, J., Cheah, K. S. E., Sham, P., Ikegawa, S. and Chan, D. (2008) Association of the Asporin D14 allele with lumbar disc degeneration in Asians. Am. J. Human Genet. 82, 744-747.
- Ho, M. S., Tsang, K. Y., Lo, R. L., Susic, M., Makitie, O., Chan, T. W., Ng, V. C., Sillence, D. O., Boot-Handford, R. P., Gibson, G., Cheung, K. M., Cole, W. G., Cheah, K. S., and Chan, D. (2007) COL10A1 nonsense and frameshift mutations have a gain-of-function effect on the growth plate in human and mouse metaphyseal chondrodysplasia type Schmid. Hum. Mol. Genet. 16, 1201-1215
- Tsang, K. Y., Chan, D., Cheslett, D., Chan W. C. W., So C. L., Melhado, I. G., Chan, T. W. Y., Kwan K. M., Hunziker E. B., Yamada, Y. Bateman, J.F., Cheung K. M. C., Cheah, K.S.E. (2007) Surviving ER stress is coupled to altered chondrocyte differentiation and function. PLoS Biology 5, e44
- Virtanen, I. M., Song, Y. Q., Cheung, K. M. C., Ala-Kokko, L., Karppinen, J., Ho, D. W. H., Luk, K. D. K., Yip, S. P., Leong, J. C. Y., Cheah, K. S. E., Sham, P., and Chan, D. (2007) Phenotypic and population differences in the association between CILP and lumbar disc disease. J. Med. Genet. 44, 285-288
- Chan, D., Song, Y., Sham, P. and Cheung, K. M. (2006) Genetics of disc degeneration. Eur. Spine J. Suppl 15, 317-325.
- Jim, J. J., Noponen-Hietala, N., Cheung, K. M., Ott, J., Karppinen, J., Sahraravand, A., Luk, K. D., Yip, S. P., Sham, P. C., Song, Y. Q., Leong, J. C., Cheah, K. S., Ala-Kokko, L., and Chan, D. (2005) The TRP2 allele of COL9A2 is an age-dependent risk factor for the development and severity of intervertebral disc degeneration. Spine 30, 2735-2742.
- Wong, Q. N. Y., Ng, V. C. W., Lin, M. C. M., Kung, H. F., Chan, D., and Huang, J. D. (2005) Efficient and seamless DNA recombineering using a thymidylate synthase A selection system in Escherichia coli. Nucleic Acids Res. 33, e59.
- Chan, D., Ho, M. S. and Cheah, K. S. (2001) Aberrant signal peptide cleavage of collagen X in Schmid metaphyseal chondrodysplasia. Implications for the molecular basis of the disease. J. Biol. Chem. 276, 7992-7997
- Aszodi, A., Chan, D., Hunziker, E., Bateman, J. F. and Fassler, R. (1998) Collagen II is essential for the removal of the notochord and the formation of intervertebral discs. J. Cell Biol. 143, 1399-1412.
- Chan, D., Weng, Y. M., Graham, H. K., Sillence, D. O. and Bateman, J. F. (1998) A nonsense mutation in the carboxyl-terminal domain of type X collagen causes haploinsufficiency in schmid metaphyseal chondrodysplasia. J. Clin. Invest. 101, 1490-1499.
- Chan, D., Cole, W. G., Chow, C. W., Mundlos, S. and Bateman, J. F. (1995) A COL2A1 mutation in achondrogenesis type II results in the replacement of type II collagen by type I and III collagens in cartilage. J. Biol. Chem. 270, 1747-1753.
- Chan, D., Cole, W. G., Rogers, J. G. and Bateman, J. F. (1995) Type X collagen multimer assembly in vitro is prevented by a Gly618 to Val mutation in the a1(X) NC1 domain resulting in Schmid metaphyseal chondrodysplasia. J. Biol. Chem. 270, 4558-4562.