My research focuses on the biological roles of glycosaminoglycans in health and in disease states. I work on the pathological processes of cancer and wound healing, as well as on the normal physiological process of mammalian spinal cord formation during embryonic development. Glycosaminoglycans are long, linear, highly negatively charged molecules made up of repeating disaccharide units of an amino sugar and an uronic acid. These molecules are often covalently linked to core protein backbones to form proteoglycans, and are ubiquitously distributed in the body. In the past, the predominant role of glycosaminoglycans in the body was thought to be structural, providing mechanical support in the extracellular matrix. However, recent studies have provided very strong evidence that glycosaminoglycans are able to interact with a large number of growth and signalling factors. Thus, they play important biological roles in regulating cell proliferation, migration, differentiation and other cellular behaviour in both physiological and pathological processes. These diverse functions are determined by variations in the glycosaminoglycan fine structure as well as by differences among core protein isoforms. The two broad aims of my research are: 1. To understand the functional roles of glycosaminoglycans in the body under normal and disease states. 2. To examine the potential usage of glycosaminoglycans as biomarkers and therapeutic targets. Specifically, my research efforts have been directed towards glycosaminoglycans in cancer, wound healing, and mammalian spinal neurulation. These are three very different but complementary biological phenomena. Both wound healing and neurulation require regulatory mechanisms for normal cellular behaviour and differentiation, while cancer is the result of cells escaping from these control processes and going awry. The knowledge obtained from studying these three areas would lead to a better understanding and appreciation of the functions of glycosaminoglycans in normal and disease states. The research programme has been featured in the NUS Research Gallery (http://www.nus.edu.sg/corporate/research/gallery/research91.htm), which regularly reports on new and exciting research conducted in the university. In addition, the importance of the research has been highlighted by the report (2008) given by the Visiting Committee/International Advisory Panel to the Yong Loo Lin School of Medicine. Cancer Cancer is one of the top three causes of death in Singapore and in many developed countries. Breast carcinoma is the commonest cancer among women. Locally, the annual incidence has tripled over the past 30 years, and currently stands at 57 per 100,000 women. Prostate carcinoma is the most frequently diagnosed cancer among men in the USA, and is the fifth commonest malignancy among Singaporean men. A better understanding of the pathological mechanisms that regulate cancer cellular behaviour would lead to the discovery of biomarkers that may be useful for diagnosis, cancer stratification and prognosis. In addition, therapeutic targets could be developed that may lead to improvements in clinical treatment of cancer patients. I examine the expression patterns and functional effects of differentially sulphated glycosaminoglycan species in breast and prostate cancers in my research. To date, the key discoveries that I have made include the use of different heparan and chondroitin sulphate species as novel biomarkers in these two cancers, and their biological roles in regulating cellular proliferation, adhesion, migration and invasion in cancer. Current efforts are directed towards further analyses of the functional roles played by different glycosaminoglycans, focusing on the signalling pathways by which they regulate cancer cell behaviour, and potentially developing them into therapeutic targets. The studies are carried out in collaboration with international and local researchers and clinicians, including: a) Prof Bay Boon Huat, Head, Department of Anatomy, NUS b) Assoc Prof Tan Puay Hoon, Head and senior consultant pathologist, Department of Pathology, Singapore General Hospital c) Assoc Prof Chia Sing Joo, Head and senior consultant urologist, Department of General Surgery, Tan Tock Seng Hospital d) Dr Martin Gotte, Head of Research and senior lecturer, Department of Obstetrics and Gynecology, Muenster University Hospital The collaboration has been highly productive, resulting in publications in prestigious international refereed journals such as Cancer Research, Journal of Pathology, Carcinogenesis, Molecular Cancer Therapeutics, Modern Pathology, and American Journal of Surgical Pathology, amongst others. Wound healing Skin wounds are one of the most common injuries throughout life. Although most skin wounds heal with little or no medical attention, a significant number requires surgical treatment each year, particularly in patients with diabetes or vascular impairment. In addition, wound healing is an important determinant of surgical success, as poor healing after surgery predisposes patients to complications such as wound breakdown, infection and septicaemia in severe cases. Conventional treatment protocols for wounds are well established, and involve cleaning and irrigating the wound to remove dirt and foreign bodies, dressing the wound, and providing haemostasis, antibiotic coverage and analgesia. More recently, scientists and clinicians have turned their attention towards promotion of the wound healing process itself, including the use of growth factors and cell-based therapies. Through a combination of in vitro work using mammalian cell cultures and in vivo experiments using a rat wound healing model, my studies have identified several candidate glycosaminoglycan species that are able to accelerate wound healing. In addition, these molecules promote angiogenesis, stimulate the production of growth factors and increase the amount of collagen laid down in the extracellular matrix of the wound tissues. Papers arising from this research have been published in Human Molecular Genetics, Journal of Molecular Medicine and Journal of Dental Research. Furthermore, the research reported in Hum Mol Genet 17, 996-1009 is currently being considered by the Eckhart-Buddecke-Stiftung (Eckhart-Buddecke Foundation) in Germany for the Pro-Scientia Prize for excellence in scientific research. Collaborators involved in this research include: a) Assoc Prof Foong Weng Chiong, Vice Dean and senior consultant dental surgeon, Department of Preventive Dentistry, NUS b) Assoc Prof Lu Jia, Head, Combat Care Laboratory, Defence Medical & Environmental Research Institute c) Assoc Prof Shabbir M Moochhala, Director of Combat Care & Performance Programme, Defence Medical & Environmental Research Institute d) Dr Dorothe Spillmann, senior scientist, Department of Medical Biochemistry and Microbiology, Uppsala University Mammalian spinal neurulation Malformations of the central nervous system are one of the commonest congenital birth defects in the world. Failure of neural tube closure results in clinically important neural tube defects, ranging from spina bifida to exencephaly and craniorachischisis. In recent years, antenatal dietary folate supplementation has helped to dramatically reduce the incidence of these defects. However, up of 30% of neural tube defects are folate-insensitive, thus burdening parents with painful decisions on abortions and long term financial, social and emotional implications of bringing up and caring for disabled children. My research has focussed on the expression and biological roles of different glycosaminoglycans in mammalian neurulation, with the aims of achieving a better understanding of neural tube formation and identification of candidate genes that may be important in neural tube defects. Besides determining the changes in expression patterns of heparan sulphate and chondroitin sulphate at different stages of neurulation, I have shown that these molecules serve important functions for neural tube closure. The work is done in collaboration with Prof Andrew Copp (Dean and Head, Neural Development Unit, Institute of Child Health, University College London), and has been published in the journal Development. A more in-depth study is currently being carried out using genomics and proteomics approaches.