Professor Danny Chan

Professor CHAN, Danny 陳振勝

BSc (Hon.), MSc, PhD (University of Melbourne)

SY and HY Cheng Professor in Stem Cell Biology and Regenerative Medicine;
Assistant Dean (Research Postgraduate Studies), LKS Faculty of Medicine

  • Office: L3-67, Laboratory Block, 21 Sassoon Road, Hong Kong
  • Email: chand@hku.hk
  • Tel: +852 3917 9482
  • Fax: +852 2855 1254
  • Web: HKU Scholar Hub

Research Interests:

  • Role of cellular stress signals in the pathogenesis of osteochondrodysplasias
  • Extracellular matrix in stem cell maintenance and differentiation
  • Generation and analysis of mouse models with skeletal abnormal abnormalities or intervertebral disc degeneration
  • Molecular mechanisms for skeletal patterning: Joint formation and digit patterning

Biography:

Graduated from the University of Melbourne, with a Bachelor of Science (degree with honours), Master of Science and PhD, Prof. Chan continued research at his alma mater on heritable skeletal disorders with a focus on extracellular matrix proteins. He joined the University of Hong Kong in 1998, maintaining his research in skeletal biology using mouse as a model to address disease mechanisms in vivo, as well as human genetic studies to define genetic risk factors for common degenerative skeletal conditions such as intervertebral disc degeneration. His research contributed to the molecular understanding of many forms of the human osteochondrodysplasias.  In recognition, he was presented with “The Premier’s Award for Health & Medical Research in Victoria, Australia; and more recently, he received the Croucher Senior Fellowship from the Croucher Foundation as recognition of his contribution to skeletal research in Hong Kong.

Research Description:

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 linear growth of long bones, the formation of a synovial joint, and the intervertebral disc of the spine. The approach is to identify novel disease genes and to model the disease in mice to define the precise molecular and developmental changes.

In addressing the molecular basis for metaphyseal chondrodysplasia type Schmid (MCDS), a human condition with an abnormal growth plate causing dwarfism, we showed that the consequence is from activating ER-stress signal in hypertrophic chondrocytes that induces a “reprogramming” event, and the cells become “rejuvenated” (11, 12). At present, we are focusing on defining the relationship between activation of ER-stress and other cellular processes including hypoxic stress signals in an integrating with cellular metabolism. 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. In address the molecular consequence of brachydactyly type A1 (BDA1), we provided novel insights 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 (9). The consequence is reduced digit outgrowth in development causing brachydactyly type A1 (BDA1) with a genetic interaction with non-canonical Wnt signaling pathway through the Ror2 receptor (6). The impact of these and copy-number variation mutations in the IHH locus (3) showed the important of precise temporal and spatial hedgehog signals for proper skeletal development. We research maintains an interest in the molecular signals that regulate joint formation with an emphasis on their regulation of progenitor cell maintenance and differentiation in the synovial joint formation.

I coordinate a Human Genetic Research Programme aiming to identify genetic risk factors for intervertebral disc (IVD) degeneration, 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. Through a candidate gene approach, we showed that Asporin as a new genetic risk factor for intervertebral disc degeneration (10), and more recently, using a combination of family linkage and genome-wide association analysis, we identified CHST3 as a novel risk factor with links to miRNA function (1). CHST3 is an important enzyme in the disc for the proper function of matrix proteins to attract water. We also use mouse as a model to understand the molecular and cellular basis of the risk factors. As such, we are interested in the developmental processes of the IVD with a focus on the impact of the risk factors altering the environmental niche of cells and potential progenitor cells in the IVD, leading to the degenerative process.

As my area of my expertise is in the 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. Planarians have extraordinary potentials to regenerate missing body parts that could provide vital clues for the developing of novel regenerative strategies.

Postgraduate Research Projects are Available in the Following Research Areas:

  • Mouse models for the understanding of rare and common skeletal defects
  • Molecular controls for skeletal patterning: Joint formation
  • Role of stress signals in cellular-decision making
  • Extracellular matrix niche in stem cell maintenance and differentiation

Danny Chan Lab

My Lab Group

DannyLab2DannyLab3

 

Selected Publications:

  1. Song, Y. Q., Karasugi, T., Cheung, K. M., Chiba, K., Ho, D. W., Miyake, A., Kao, P. Y., Sze, K. L., Yee, A., Takahashi, A., Kawaguchi, Y., Mikami, Y., Matsumoto, M., Togawa, D., Kanayama, M., Shi, D., Dai, J., Jiang, Q., Wu, C., Tian, W., Wang, N., Leong, J. C., Luk, K. D., Yip, S. P., Cherny, S. S., Wang, J., Mundlos, S., Kelempisioti, A., Eskola, P. J., Mannikko, M., Makela, P., Karppinen, J., Jarvelin, M. R., O'Reilly, P. F., Kubo, M., Kimura, T., Kubo, T., Toyama, Y., Mizuta, H., Cheah, K. S., Tsunoda, T., Sham, P. C., Ikegawa, S., and Chan, D. (2013)  Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant. J. Clin. Invest 123:4909-4917
  2. Sakai, D., Nakamura, Y., Nakai, T., Mishima, T., Kato, S., Grad, S., Alini, M., Risbud, M. V., Chan, D., Cheah, K. S., Yamamura, K., Masuda, K., Okano, H., Ando, K., and Mochida, J. (2012) Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc. Nat. Commun. 3, 1264
  3. Klopocki E., Lohan S., Brancati F., Koll R., Brehm A., Seemann P., Dathe K., Stricker S., Hecht J., Bosse K., Betz R. C., Garaci F. G., Dallapiccola B., Jain M., Muenke M., Ng V. C., Chan W., Chan D., and Mundlos S. (2011) Copy-number variations involving the IHH locus are associated with syndactyly and craniosynostosis, Am. J. Hum. Genet. 88, 70-75
  4. Spielmann, M., Brancati, F., Krawitz, P. M., Robinson, P. N., Ibrahim, D. M., Franke, M., Hecht, J., Lohan, S., Dathe, K., Nardone, A. M., Ferrari, P., Landi, A., Wittler, L., Timmermann, B., Chan, D., Mennen, U., Klopocki, E., and Mundlos, S. (2012) Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus. Am. J. Hum. Genet. 91, 629-635 (Recommended by Faculty of 1000)
  5. Leung V.Y.L., Gao B., Dung N.W.F., Leung K.K.H., Wynn S.L, Niewiadomska R. A., Lau J.Y.B., Melhado I., Chan D., Cheah K.S.E. (2011) SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression. PLOS Genetics 7(11): e1002356
  6. Witte F., Chan D., Economides A.N., Mundlos S. and Stricker S. (2010) Receptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region. PNAS 107: 14211-14216 
  7. 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
  8. 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
  9. 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 (Recommended by Faculty of 1000)
  10. 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
  11. 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
  12. 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 endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function. PLoS Biology 5, e44 (Recommended by Faculty of 1000)
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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.
  18. 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
  19. 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
  20. 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 1(X) NC1 domain resulting in Schmid metaphyseal chondrodysplasia. J. Biol. Chem. 270, 4558-4562

Media Coverage of Research

RGC/External Projects:

As Principal Investigator:    
Project Title Funding Source Start Date
Progenitor cells in the formation and repair of articular cartilage General research fund 2014
脊柱发育与稳态维持的细胞分子机制研究 973 programe 2014
Interplay between ER stress and hypoxic stress in the regulation of chondrocyte differentiation General research fund 2012
Discovering the genetics, understanding progenitor cell niche and transcriptional controls to harness the endogenous regeneration potentials of the intervertebral disc AOSPINE International 2012
Functional analyses of how genomic variation affects personal risk for degenerative skeletal disorders Theme Base Research Scheme 2012
     
As Co-Investigator:    
Project Title Funding Source Start Date
Identifying critical transitions and gene regulatory networks controlling phases of chondrocyte differentiation in the growth plate NSFC/RGC 2014
Mechanistic insights into the genesis and physiological role of hypertrophic chondrocyte-derived osteoblasts  GRF 2014
The role of silver nanoparticles in tendon healing GRF 2013
Development of novel biodegradable bone substitutes for osteoporotic spinal fracture treatments GRF 2013
Metabonomics of intervertebral disc degeneration GRF 2013
The role of adipokines in intervertebral disc degeneration of the lumbar Spine GRF 2012
Role of cadherin 2 in intervertebral disc development and degeneration GRF 2012

Lab Personnel:

  • Research Fellow/Associate
    • Wilson Chan
    • Matheusz Kudelko
    • Alvin Lee
    • Andrea Ng
    • Vivian Tam
    • Sara Wang
    • Simon Yip
  • Research Assistant
    • Serena Xiong
  • Technicans
    • Alice Lui
    • Jacky Yeun
  • Research Postgraduate Students
    • Amy Feng (PhD)
    • Yan Lam (PhD)
    • Yulianna Lie (PhD)
    • Sophia Ma (MPhil)
    • Shirley Shen (PhD)
    • Gary Wong (MPhil)
    • Angela Yao (PhD)
    • Joyce Zhang Ying (PhD)
  • Final Year Project Students
    • Seria Chan
    • Akansha Mahavir
    • Derek Chan
  • Student Interns
    • Winnie Tong