Day 1 :
University of British Columbia & PROOF Centre of Excellence, Canada
Scott J Tebbutt is an Associate Professor in the Department of Medicine, University of British Columbia and Principal Investigator at the Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, Canada. His research program is focused on molecular signatures of complex respiratory disease, including the early and late reactions in atopic asthma and allergic rhinitis. He is also the Chief Scientific Officer of the Prevention of Organ Failure (PROOF) Centre of Excellence. His responsibilities include evaluating new, high-performance technologies to improve biomarker discovery, as well as computational biology approaches to better deal with cell type heterogeneity and integration of OMIC datasets. He holds BA in Biochemistry from the University of Oxford and PhD in Molecular Genetics from the University of East Anglia, Cambridge Laboratory at John Innes Centre.
Systems biology combines information from different molecular layers to provide a holistic view of a biological system and unravel its complexities. Integration of data across these layers requires methods that include multivariate approaches, Bayesian methods and network analyses. Although metabolomic analysis can provide a valuable ‘snapshot’ of biochemical processes at a high level, it is the functional relationships among various additional elements including genes, proteins and cells that will provide a deeper understanding of the biology. Indeed, any single OMICs approach is unlikely to suffice to characterize the complexity of biological processes in health and disease. We are developing innovative OMIC integration via functional bioinformatics and data-driven statistical approaches and computational modeling to identify signals in complex OMICs datasets regarding mechanisms that drive biological processes in a variety of human health and disease conditions.
CMU, NHRI and NTHU, Taiwan
Kenneth K Wu has received his MD from National Taiwan University, Taipei, Taiwan, MS from Yale University New Haven, CT, USA and PhD in Pharmacology from University of London, UK. He was the Huffington Chair and Director of Hematology Division at University of Texas Health Science Center at Houston and Distinguished Investigator and Former President of National Health Research Institutes (NHRI), Taiwan. He is currently a Distinguished Professor and Director of Metabolomic Medicine Research Center at CMU, Taiwan. He holds Ho Jin Dui Chair at NTHU and Distinguished Chair at National Taiwan University, Taiwan. His research interests have centered on thrombosis, vascular biology and prostaglandin synthesis and regulation. He is a Member of several distinguished academic societies and has received international recognitions and awards.
Statement of the Problem: Overexpression of cyclooxygenase-2 (COX-2) and pro-inflammatory (PI) cytokines is a major contributor to human systemic inflammatory disorders and cancer metastasis. Expression of COX-2 and PI cytokines are regulated by transcriptional mechanisms, but it remained unclear whether it is endogenously controlled by small molecules.
Conceptual & Experimental Orientation: We suspected that human cells such as fibroblasts release soluble factors into the extracellular milieu which act in a paracrine manner to control COX-2 and PI cytokine expression. Soluble factors isolated from normal cells inhibit COX-2 overexpression in inflammatory and cancer cells. NMR analysis suggests that the soluble factors contain indole moiety. We named the factors cytoguardins. We subsequently found that cancer cells do not release cytoguardins. Comparative metabolomics analysis coupled with molecular genetics and biochemical studies identify 5-methoxytryptophan (5-MTP) as a cytoguardin. Endothelial cells (ECs) produce abundant 5-MTP which accounts for a high human serum level of 5-MTP. 5-MTP is a powerful innate factor defending against systemic inflammation and cancer cell metastasis. Compromised 5-MTP production due to insulting agents such as LPS results in COX-2 and cytokine storm, organ failure and death in animal models. Administration of 5-MTP attenuates cytokine storm and prevents organ failure and death. 5-MTP inhibits cancer cell migration and EMT in vitro and cancer metastasis in murine xenograft tumor model. 5-MTP exerts its biological actions in part by blocking p38 MAPK, p300 HAT and NF-kB activation.
Conclusion & Significance: Human cells such as fibroblasts and endothelial cells produce and release 5-MTP to maintain inflammatory homeostasis and control cancer metastasis by inhibiting the expression of COX-2 and PI genes. It represents a new class of protective molecules and a valuable lead compound for developing new drugs against systemic inflammatory disorders and cancer metastasis.