IMCB Adjunct PIs

Melissa FULLWOOD

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	Melissa FULLWOOD 3D genome organization Lab
Melissa FULLWOOD Melissa Fullwood completed her B.Sc. (Honours) in Biological Sciences at Stanford University and received her Ph.D. from the NUS Graduate School for Integrative Sciences and Engineering (NGS) at the Genome Institute of Singapore. She was a Lee Kuan Yew Post-Doctoral Fellow at Duke-NUS. She became an Assistant Professor at Yale-NUS and a Special Fellow at the Cancer Science Institute in 2012. Following the award of a National Research Foundation Fellowship in 2013, she became a Junior Principal Investigator at the Cancer Science Institute. She became an Assistant Professor in School of Biological Sciences, Nanyang Technological University, in 2015, and was promoted to Associate Professor with tenure in 2022. She was a recipient of the Agency for Science, Technology and Research (A*STAR) National Science Scholarships, a recipient of the L'Oreal-UNESCO for Women in Science National Fellowship Singapore in 2009, and the international winner of the GE and Science prize in 2010. Melissa is a co-inventor on two patents on chromatin interaction analysis with paired-end tag sequencing (ChIA-PET).
Research Publications

Albert CHEN

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Albert CHEN

Assistant Professor, School of Biological Sciences

Email: albert.chen@ntu.edu.sg

Biography
Albert Chen is an Assistant Professor in the School of Biological Sciences. He received his undergraduate degree at the University of Illinois at Urbana-Champaign and Ph.D. from Columbia University where he examined the specification of motor neuron subtype identity and sensory neuron axonal targeting in the spinal cord. As a postdoctoral fellow at the University of California, San Francisco, he transitioned to studying supraspinal motor structures, exploring the molecular mechanisms underlying the assembly and maintenance of neural circuits in the cerebellum, a brain region critical for sensorimotor integration and voluntary motor control.

Research Interest
Research in the Chen Lab employs a multidisciplinary approach to pursue two major aims: 1) to define the molecular, anatomical, and functional distinctions of neuronal subpopulations in the nervous system that control specific behaviors; and 2) to identify and characterize genes that direct the assembly and maintenance of neural circuits. These general issues are examined through the analysis of local and long-range circuits in subcortical brain centers important for coordination and refinement of movement, motor learning, and cognitive behaviors using genetic and viral circuit tracing, neural manipulations, and behavioral approaches in mice.

Current Projects

Control of discrete and rhythmic movement by cerebello-thalamo-cortical circuits
Defining the brain circuitry defects that cause dementia
Neurotrophic factors and the assembly of inhibitory circuits in the cerebellum
The Role of Cadherin-13(CDH13) in the Development and Function of the Brain Circuitry and Its Implication for Autism Spectrum Disorders (ASDs)
Warwick-NTU Neuroscience Research @ Singapore (WN2R@S) On Opto-Genetic Tools For Investigating Glial Cell
Biology(Principal Investigators: Asst Prof Albert I. Chen and AsstProf Ayumu Tashiro)

Selected Publications

Kamath, S.P. and Chen, A.I. (2018). Myocyte enhancer factor 2c regulates dendritic complexity and connectivity of cerebellar Purkinje cells. Molecular Neurobiology, s12035, 1-18.
Tan, S., Xiao, Y., Yin, H.H., Chen, A.I., Soong, T.W., Je, H.S. (2018). Postnatal TrkB ablation in corticolimbic interneurons induces social dominance in male mice. Proceedings of the National Academy of Sciences of the United States of America (PNAS), pnas.1812083115.
Low, A.Y.T.*, Thanawalla, A.R.*, Yip, A.K.K.*, Kim, J., Wong, K.L.L., Tantra, M., Augustine, G.J. and Chen, A.I. (2018). Precision of discrete and rhythmic forelimb movements requires a distinct neuronal subpopulation in the interposed anterior nucleus. Cell Reports, 22(9), 2322-2333. *these authors contributed equally.
Tantra, M.*, Guo, L.*, Kim, J., Zainolabidin, N., Eulenburg, V., Augustine, G.J., Chen, A.I. (2018). Conditional deletion of Cadherin-13 perturbs Golgi cells and disrupts social and cognitive behaviors. Genes, Brain and Behavior, e12466, *these authors contributed equally.
Zainolabidin, N., Kamath, S.P., Thanawalla, A.R., Chen, A.I. (2017). Distinct activities of Tfap2A and Tfap2B in the specification of GABAergic interneurons in the developing cerebellum. Frontiers in Molecular Neuroscience, 10(281).

Jianzhu CHEN

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Jianzhu Chen, PhD

Professor of Biology

KI Research Areas of Focus:
Cancer Immunology

room 76-261A
phone (617) 258-6173
email jchen@mit.edu

Chen Lab
phone (617) 324-5100
fax (617) 258-6172
website

Administrative Assistant:
Ryan Hayman
phone (617) 253-0796
email rhayman@mit.edu

"We seek to understand the cellular and molecular mechanisms underlying the development and function of the immune system. Our goal is that the knowledge we gain will lead to more effective immunotherapies for cancer and other diseases. Our laboratory focuses on a particular class of immune cells – CD8 T-cells –which play an important role in the ability of the immune system to respond more strongly to threats that have been encountered before. We investigate CD8 T –cell responses to the influenza virus and to prostate cancer. Our laboratory is also actively engaged in developing improved mouse models of the human immune system, so that our experimental systems most closely reflect the clinical reality."

In addition to being a professor at MIT, Dr. Chen is also a co-director of the Center for Infection and Immunity, the Chinese Academy of Sciences. He received a received a B.S. degree from Wuhan University in China and a Ph.D. in Genetics from Stanford University in 1990. He was a post-doctorial fellow and then an instructor at Harvard Medical School before he joined the MIT faculty in the Department of Biology.

Further Information
Research Summary
Cellular and Molecular Basis of Immunological Memory
Immunological memory is the ability of lymphocytes to respond faster and more strongly to reencounter of the same antigen. It is a central feature of the adaptive immunity and is the basis of vaccination. However, little is known about the differentiation, maintenance, reactivation, and function of memory T cells. We have shown that as naïve CD8 T cells undergo proliferation in lymphopenic mice in the absence of overt antigenic stimulation, they progressively acquire phenotypic and functional characteristics of antigen-induced memory CD8 T cells. We have also developed mouse models in which CD8 T cell response to influenza virus infection can be studied at any time and in any anatomical locations. Using this model, we have identified factors that promote the development and maintenance of central versus effector memory T cells. In the long-term, we are interested in elucidating the molecular pathways of memory CD8 T cell development and identifying conditions for the optimal induction and maintenance of CD8 memory T cells for vaccination.

CD8 T Cell Responses to Prostate Cancer
CD8 T cells are critical for the clearance of virus infection as well as tumor cells. Harnessing the power of CD8 immunity to kill tumor cells has been a long-term goal of cancer immunotherapy. We have developed a mouse model in which CD8 T cell response and tolerance to a spontaneous prostate cancer can be monitored in detail. We have shown that tumor-specific CD8 T cells can be activated in tumor-bearing mice by virus infection. Although the resulting effector CD8 T cells infiltrate prostate tumor and remain functional in the tumor tissue for several days, eventually the T cells are inactivated or tolerized in the tumor environment. Interestingly, a population of tumor-specific CD8 T cell persists in the tumor tissue, analogous to the tumor-infiltrating lymphocytes in human. We are investigating the basis for the persistence of tumor-specific CD8 T cells in the tumor tissue and developing approaches to delay the tolerance induction and reactivate the persisting tolerized CD8 T cells. Findings from these studies may help develop more effective cancer immunotherapy.

Development of a Robust Humanized Mouse Model
There has been a great need to study human immune responses to pathogenic infections in a systematic and controlled manner. For this reason, tremendous efforts have been devoted to reconstitute severe combined immunodeficient (scid) mice, which lack their own T and B lymphocytes, with human immune cells. However, early approaches were unsuccessful because of poor implantation efficiency, or rapid disappearance of human T and B cells from recipient mice, or rapid development of hematopoietic malignancies in recipient mice. A breakthrough was reported recently by using scid mice that were also deficient in the common gamma chain. Although the existing humanized mouse model begins to allow establishment of infection models of human pathogens, such as HIV, the current system is far from optimal. First, only a small cohort of humanized mice (~10) can be constructed with HSCs from a single cord blood. This number is too small for any significant study. Second, reconstitution of myeloid cells, which mediate innate immune responses, is generally poor in the humanized mice. Third, HSCs have not been easily amenable to genetic modification, which is critical for studying gene function in immune responses to specific pathogens. We have made breakthroughs in overcoming the three limitations. First, we have developed two methods to expand HSCs in vitro so that large number of humanized mice can be made using HSCs from the same source. Second, we have devised a simple method to enhance reconstitution of specific subset of myeloid cells in reconstituted mice by expressing appropriate human cytokines. Third, we have developed methods to genetically modify HSCs prior to their transfer into NSG mice. As a proof-of-concept, we have introduced proto-oncogenes into HSCs and developed a human B cell leukemia/lymphoma model in mice. Development of a better humanized mouse model will provide an important tool for studying human immune responses and diseases in a small animal model.

Selected Publications
Kaur M, Drake AC, Hu G, Rudnick S, Chen Q, Phennicie R, Attar R, Nemeth J, Gaudet F, Chen J. Induction and Therapeutic Targeting of Human NPM1c+ Myeloid Leukemia in the Presence of Autologous Immune System in Mice. J Immunol. 2019 Mar 15;202(6):1885-1894. doi: 10.4049/jimmunol.1800366. Epub 2019 Feb 1. PMID: 30710044

Drake A, Kaur M, Iliopoulou BP, Phennicie R, Hanson A, Chen J. Interleukins 7 and 15 Maintain Human T Cell Proliferative Capacity through STAT5 Signaling. PLoS One. 2016 Nov 17;11(11):e0166280. doi: 10.1371/journal.pone.0166280. eCollection 2016. PMID: 27855183

Roghanian A, Fraser C, Kleyman M, Chen J. B Cells Promote Pancreatic Tumorigenesis. Cancer Discov. 2016 Mar;6(3):230-2. doi: 10.1158/2159-8290.CD-16-0100. PMID: 26951836

Chen Q, Ye W, Jian Tan W, Mei Yong KS, Liu M, Qi Tan S, Loh E, Te Chang K, Chye Tan T, Preiser PR, Chen J. Delineation of Natural Killer Cell Differentiation from Myeloid Progenitors in Human.Sci Rep. 2015 Oct 12;5:15118. doi: 10.1038/srep15118. PMID: 26456148

Li Y, Shen C, Zhu B, Shi F, Eisen HN, Chen J. Persistent Antigen and Prolonged AKT-mTORC1 Activation Underlie Memory CD8 T Cell Impairment in the Absence of CD4 T Cells. J Immunol. 2015 Aug 15;195(4):1591-8. doi: 10.4049/jimmunol.1500451. Epub 2015 Jul 10. PMID: 26163589

Bak SP, Barnkob MS, Wittrup KD, Chen J. CD8+ T-cell responses rapidly select for antigen-negative tumor cells in the prostate. Cancer Immunol Res. 2013 Dec;1(6):393-401. doi: 10.1158/2326-6066.CIR-13-0109. Epub 2013 Sep 20. PMID: 24778132

Hu G, Chen J. A genome-wide regulatory network identifies key transcription factors for memory CD8⁺ T-cell development. Nat Commun. 2013;4:2830. doi: 10.1038/ncomms3830. PMID: 24335726

Chen Q, Khoury M, Chen J. Expression of human cytokine genes dramatically improves reconstitution of specific human blood lineage cells in humanized mice. Proc Natl. Acad. Sci. USA,2009;106:21783-21788.

Bai A, Higham E, Wittrup D, Eisen HN, Chen J. Rapid tolerization of tumor-infiltrating effector T cells in the prostate of TRAMP mice. Proc. Nat. Acad. Sci. USA, 2008;105:13003-8.

Shen C-H, Ge Q, Talay O, Eisen HN, Garcia-Sastre A, Chen J. Loss of interleukin (IL)-7 and IL-15 receptors is associated with disappearance of memory CD8 T cells in respiratory track. J. Immunol. 2008;180:171-8 (2008).

Cho B, Varada R, Ge Q, Eisen HE, Chen J. Homeostasis-stimulated proliferation drives naïve T cells to differentiate directly into memory cells. J. Exp. Med. 2000;192:549-556.

Search PubMed for Chen lab publications

Vincent CHOW

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Associate Professor Vincent T. K. Chow

DipMicrobiol, MD, FRCPath, MBBS, MSc, PhD
Associate Professor
Department of Microbiology and Immunology

Tel: 6516-3691
Email: micctk@nus.edu.sg

Research Interest

Host and Pathogen Interactivity Laboratory

Mouse models for understanding the molecular pathogenesis of influenza and pneumococcal pneumonia.
Activation and formation of neutrophil extracellular traps in severe influenza and secondary pneumococcal pneumonia.
Genomics and proteomics of emerging and re-emerginginfectious diseases.
Vaccine strategies, molecular surveillance and seroepidemiology of microbial infections.

Our laboratory is engaged in Molecular Genetics and Infectomics – the interface between emerging and re-emerging viral pathogens and host genes and proteins. A major focus is to adopt genomic and proteomic strategies for studying the infectomics of viruses/diseases such as influenza, enterovirus 71, dengue, SARS coronavirus, and human herpesvirus 6. The goal is to identify and analyse critical interactions between medically important viruses and host proteins that contribute to pathogenesis. We focus on the molecular genetics and infectomics of influenza pneumonia and of hand, foot and mouth disease, specifically on the cellular, molecular, and viral pathogenesis of severe influenza and enterovirus 71 infections.

The overall theme of our research on influenza is “Virology and immunology of human influenza and mouse models of influenza”. Our murine models of severe influenza pneumonia facilitate infectomics studies on influenza in vivo. These animal models are also harnessed to identify critical mutations in the influenza H3N2 virus that can enhance its virulence. The contributions of excessive cytokine signalling molecules and oxidative stress to lung damage during influenza pneumonia are also studied, with a view to countering their deleterious effects. Another key area is the repair of new lung tissue following damage by influenza infection, and testing novel therapies including growth factors to accelerate the regeneration of lung epithelium. Specific projects include: the role of neutrophil extracellular traps in pathogenesis; expression of influenza and other microbial antigens; human influenza monitoring, surveillance, molecular epidemiology and evolution.

We actively collaborate with clinicians, infectious disease physicians, laboratory medicine specialists, epidemiologists, basic scientists, bioengineers, chemists, and statisticians on key areas of influenza and pneumonia research. Pertinent examples of such research activities are: sequencing of viral genomes to study their epidemiology and evolution; identification of host biomarkers of severe influenza pneumonia; and pneumococcal pneumonia secondary to influenza. We are also studying the dynamics of influenza transmission in households, schools, hospitals, elderly homes, and in the community. Other studies include: evaluation of influenza vaccine efficacy in different age groups ranging from young to elderly subjects (including their antibody and cell-mediated immune responses); the waning of immunity with time; clarifying the uptake and utility of vaccination in reducing morbidity and mortality especially in high-risk groups.

Together with a multidisciplinary group of researchers, our team has developed and applied molecular tools for rapid diagnosis and molecular epidemiological surveillance of important human pathogens, including influenza, dengue viruses, enterovirus 71, human papillomaviruses, mumps virus, respiratory syncytial virus, varicella-zoster virus, Neisseria gonorrhoeae and Chlamydophila pneumoniae.

Previously, our Human Genome Laboratory has isolated and characterised several novel human genes and proteins, including HEP-COP (alpha-subunit of the coatomer protein complex); DENN (differentially expressed in normal and neoplastic cells); HUEL (SLC30A9, a member of the solute carrier superfamily); HALR (MLL3 associated with leukaemia); and MOST-1 (overexpressed/amplified in high grade cancers of the breast and prostate).

Representative Publications

Rai P, Parrish M, Tay IJ, Li N, Ackerman S, He F, Kwang J, Chow VT, Engelward BP (2015) Streptococcus pneumoniae secretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells. Proceedings of the National Academy of Sciences, USA, 112(26): E3421-30.

Li L, Chong HC, Ng SY, Kwok KW, Teo Z, Tan EH, Choo CC, Seet JE, Choi HW, Buist ML, Chow VT, Tan NS (2015) Angiopoietin-like 4 increases pulmonary tissue leakiness and damage during influenza pneumonia. Cell Reports, 10: 654-663.

Tan KS, Choi H, Jiang X, Yin L, Seet JE, Patzel V, Engelward BP, Chow VT (2014) Micro-RNAs in regenerating lungs: an integrative systems biology analysis of murine influenza pneumonia. BMC Genomics, 15: 587.

Narasaraju T, Yang E, Samy RP, Tan KS, Moorthy AN, Phoon MC, van Rooijen N, Choi HW, Chow VT (2014) Combination therapy with hepatocyte growth factor and oseltamivir confers enhanced protection against influenza viral pneumonia. Current Molecular Medicine, 14(5): 690-702.

Narayana Moorthy A, Narasaraju T, Rai P, Perumalsamy R, Tan KB, Wang S, Engelward B, Chow VT (2013) In vivo and in vitro studies on the roles of neutrophil extracellular traps during secondary pneumococcal pneumonia after primary pulmonary influenza infection. Frontiers in Immunology, 4: 56.

Ivan FX, Tan KS, Phoon MC, Engelward BP, Welsch RE, Rajapakse JC, Chow VT (2013) Neutrophils infected with highly virulent influenza H3N2 virus exhibit augmented early cell death and rapid induction of type I interferon signaling pathways. Genomics, 101(2): 101-112.

Ng HH, Narasaraju T, Phoon MC, Sim MK, Seet JE, Chow VT (2012) Doxycycline treatment attenuates acute lung injury in mice infected with virulent influenza H3N2 virus: involvement of matrix metalloproteinases. Experimental & Molecular Pathology, 92(3): 287-295.

Narasaraju T, Yang E, Samy RP, Ng HH, Poh WP, Liew AA, Phoon MC, van Rooijen N, Chow VT (2011) Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. American Journal of Pathology, 179(1): 199-210.

Narasaraju T, Ng HH, Phoon MC, Chow VT (2010) MCP-1 antibody treatment enhances damage and impedes repair of the alveolar epithelium in influenza pneumonitis. American Journal of Respiratory Cell & Molecular Biology, 42(6): 732-743.

Narasaraju T, Sim MK, Ng HH, Phoon MC, Shanker N, Lal SK, Chow VT (2009) Adaptation of human influenza H3N2 virus in a mouse pneumonitis model: insights into viral virulence, tissue tropism and host pathogenesis. Microbes & Infection, 11(1): 2-11.

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FU Xin-Yuan

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FU Xin-Yuan
Professor

Tel: +65 6516 7996
Email: bchfxy@nus.edu.sg

Affiliations

Professor, Department of Biochemistry, Yong Loo Lin School of Medicine, NUS.
Professor, Department of Biological Sciences, Faculty of Sciences, NUS.
Senior Principal Investigator, Cancer Stem Cells Programme, Cancer Science Institute of Singapore.
Supervisor, NUS Graduate School for Integrative Sciences and Engineering (NGS), NUS.

Education

Degree and Institution	Year(s)
Postdoctoral: Rockefeller University New York, USA	1988-1991
Ph.D. Molecular Biology from Columbia University	1988

Professional Experience

Title	Year(s)
Director of International Relation (China), Yong Loo Lin School of Medicine, National University of Singapore	2011–present
Professor, Department of Biochemistry,Yong Loo Lin School of Medicine, National University of Singapore	2008–present
Senior Principal Investigator, Cancer Science Institute of Singapore, National University of Singapore	2008–present
Head, Department of Biochemistry,Yong Loo Lin School of Medicine, National University of Singapore	2008–2011
Professor, Microbiol and Immunology, Indiana University School of Medicine	2004–present
Associate Professor, Member, Yale Cancer Center, Yale University, New Haven, CT	1996–2003
Assistant Professor, Pathology, Yale University School of Medicine	1994-1996
Assistant Professor, Mount Sinai School of Medicine, New York	1992-1994

Research Interest

* Molecular mechanisms of STAT3 in regulation of tumorigensis, metastasis and angiogenesis
* The key functions of STAT proteins in epigenetic regulation of stem cells, development and diseases
* Reprogramming mechanisms during early development and generation of adult stem cells
* Mechanisms of neural development, gene circuitry for formation of cognition and related diseases

In particular, we are pursuing the following projects:

1) To investigate the critical roles of endothelial STAT3 in tumour angiogenesis. We have created an endothelial cell (EC)-specific deletion in STAT3 (STAT3E–/– for ECs) to study the pathophysiological functions of EC-expressed STAT3 in vivo. Possible epigenetic alterations induced by STAT3 activity will be examined.

2) To reveal the molecular mechanisms of tumour metastasis and the role of STAT3 during this process. Tumour metastasis involves invasion; tumour cell dissemination through blood vessels or the lymphatic system; colonization of distant organs; and, finally, the outgrowth of metastases. We are investigating the possible molecular bases responsible for this STAT3 mediated metastasis.

3) A novel direction of the lab is to investigate whether tumourigenesis can be affected via inflammation regulated by STAT3. We are investigating a hypothesis that STAT3, as an oncogene, can regulate epigenetic factors during T helper cell-mediated inflammation and cause tumourigenesis. We plan to systematically investigate the manner in which inflammatory responses cause epigenetic alterations and to study their effects on cancer development.

4) The regulatory roles of STAT proteins in stem cells. In my laboratory, we have recently developed systems using Embryonic Stem (ES) cells and Induced Pluripotent Stem (iPS) cells. We have established different in vitro developmental systems particularly in neurogenesis and hematopoiesis. The objectives are to reveal epigenetic mechanisms that are controlled through STAT signaling to specific gene regulatory circuitries.

Selected Publications

Fu, X.-Y, Schindler, C., Improta, T., Aebersold, R. and Darnell, J. E.(1992) The proteins of ISGF3, the IFN-alpha induced transcriptional activator, define a gene family involved in signal transdution. Proc. Natl. Acad. Sci. USA, 89:7840-7843. (This paper described original cloning of the first two STAT genes).

Fu, X.-Y. A transcription factor with SH2 and SH3 domains is directly activated by an interferon-alpha-induced cytoplasmic protein tyrosine kinase(s). Cell. 1992 Jul 24; 70(2):323-335. (This paper described original discovery of the mechanism of STAT signaling pathway).

Fu, X.-Y and Zhang JJ. Transcription factor p91 interacts with the EGF receptor and mediates activation of the c-fos gene promoter. Cell. 1993 Sep 24, 74(6):1135-1145.

Chin EY, Kitagawa M, Su WS, You ZH, Iwamoto Y and Fu, X.-Y. Cell Growth Arrest and Induction of Cyclin Dependent Kinase Inhibitor p21WAF1/CIP1 Mediated by STAT1. Science. 1996 May 3; 272(5262):719-22.

Su WCS, Kitagawa M, Xue N, Xie B, Garofalo S, Cho J, Deng C, Horton WA and Fu, X.-Y. Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature. 1997 Mar 20; 386(6622):288-92.

Welte T, Leitenberg D, Dittel BN, al-Ramadi BK, Xie B, Chin YE, Janeway CA, Bothwell AL, Bottomly K, Fu, X.-Y. STAT5 interaction with the T cell receptor complex and stimulation of T cell proliferation. Science. 1999 Jan 8; 283(5399):222-5.

Welte T, Zhang SS, Wang T, Zhang Z, Hesslein DG, Yin Z, Kano A, Iwamoto Y, Li E, Craft JE, Bothwell AL, Fikrig E, Koni PA, Flavell RA, Fu, X.-Y. STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci U S A. 2003 Feb 18; 100(4):1879-84.

Kano, A., Wolfgang, M., Gao, Q., Zhang, S. S-M. Iwamoto, Y., Pober, J., Flavell, R. A. and Fu, X.-Y. (2003) Endothelial cells require Stat3 for protection against endotoxin-induced inflammation Journal of Experimental Medicine, 198, 1517-1525.

Laouar*, Y., Welte*, Fu, X.-Y.** and Flavell, R. A. (2003) Flt3 ligand specifically requires Stat3 in the induction of dendritic cell development from hematopoietic stem cells Immunity, 19, 849–861. *These authors contribute equally to this work. ** The Corresponding Author.

Gao Q, Wolfgang MJ, Neschen S, Katsutaro Morino, Tamas L. Horvath, Shulman G, & Fu, X.-Y. (2004). Disruption of Neural Stat3 Causes Obesity, Diabetes, Infertility and Thermal Dysregulation Proc. Natl. Aca. Sci. USA 101, 4661–4666.

Liu, L, Song, L., Yu, X-Z., Li, T. S., Li, Z. G., Chen, P. L., Li, Y. H.,, Wang, S. D. ., Chen, Y., Chang, Z. J. and Fu, X.-Y. (2004) A novel protein tyrosine kinase NOK that shares homology with PDGF/FGF receptors, induces tumorigenesis and metastasis in nude mice. Cancer Research 64, 3491-3499.

Chow, EK, O’Connell, R.M., Schilling, S., Wang, X. F., Fu, X.-Y. and Cheng G., (2005) TLR agonists regulate PDGF-B production and cell proliferation through TGF-b/type I IFN crosstalk. EMBO J, 24, 4071–4081.

Rong Y, Cheng L, Chang Z, and Fu, X.-Y. WT1 and STAT3 synergistically promote cell proliferation: A possible mechanism in sporadic Wilms' tumor. Cancer Research. 2006 Aug 15; 66(16):8049-57.

Kim BG, Li C, Qiao W, Mamura W, Kasperczak B, Anver M, Wolfraim L, Hong S, Mushinski E, Kim SG, Fu, X.-Y, Deng C and Letterio JJ. SMAD4 signaling in T cells is required for suppression of gastrointestinal cancer. Nature 2006 Jun 22; 441(7096):1015-9.

Wang M, Zhang W, Crisostomo P, Markel T, Meldrum KK, Fu, X.-Y, Meldrum DR. (2007) Endothelial STAT3 plays a critical role in generalized myocardial proinflammatory and proapoptotic signaling. Am J Physiol Heart Circ Physiol. 293(4):H2101-8. Epub 2007 Aug 3.

Moh, A., Zhang, W., Wang, Z., Wang, J. and Fu, X.-Y (2008) STAT3 sensitizes insulin signaling by negatively regulating GSK-3β. Diabetes. 57(5):1227-35. Epub 2008 Feb 11.

Cohen P. A., Koski, G.K., Czerniecki, B.J., Bunting, K.D., Fu, X.-Y, Wang, Z., Zhang W.J. et al., (2008) STAT3- and STAT5-dependent pathways competitively regulate the pan-differentiation of CD34 pos cells into tumor-competent dendritic cells. Blood, 112(5):1832-43. Epub 2008 Jun 24.

Wegrzyn, J., Potla, R., Chwae, Y-J, Fu, X.-Y., Larner, A. C etc (2008) A Novel Function of Stat3 in Cellular Respiration. Science, 323(5915): 793-7. Epub 2009 Jan 8. 5).

Zhang W, Chan RJ, Chen H, Yang Z, He Y, Zhang X, Luo Y, Yin F, Moh A, Miller LC, Payne RM, Zhang ZY, Fu, X.-Y, Shou W. (2009) Negative regulation of Stat3 by activating PTPN11 mutants contributes to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia. J Biol Chem. 284(33):22353-63. Epub 2009 Jun 9.

Fukuda S, Singh P, Moh A, Abe M, Conway EM, Boswell HS, Yamaguchi S, Fu, X.-Y, Pelus LM. Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal-tandem-duplication of Flt3. (2009) Blood. 114(2):394-403.

Wang, H, O Park, F Lafdil, K Shen, N Horiguchi, S Yin, X-Y FU, G Kunos and B Gao, "Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity". HEPATOLOGY, 51, no. 4 (2010): 1354-1362. (United States). (PMID: 20041412).

Charlie Mantel, Steven Messina-Graham, Akira Moh, Scott Cooper, Giao Hangoc, Xin-Yuan Fu, and Hal E. Broxmeyer. (2012) Hematopoietic cell-targeted STAT3 Deletion: Stem/Progenitor Cell Defects, mitochondrial dysfunction, ROS overproduction, and a rapid aging-like phenotype. Blood, 120(13):2589-99. Epub 2012 Jun 4

Dang Vinh Do, Jun Ueda, Chanchao Lorthongpanich, Wenjun Zhang , Akira Moh , Yi Zhou, Bo Feng, Guoji Guo, Peiyu J Lin, Md Zakir Hossain, Daniel M. Messerschmidt , Qiang Wu, Paul Robson, Huck Hui Ng, Lorenz Poellinger, Barbara B. Knowles, Davor Solter and Xin-Yuan Fu. A Genetic and Developmental Pathway from STAT3 to the OCT4-NANOG Circuit Essential for Maintenance of ICM Lineages in vivo. Genes & Development, 2013 Jun 15;27(12):1378-90. doi: 10.1101/gad.221176.113.PMID: 23788624

Kong Peng LAM

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PROF LAM KONG PENG
Executive Director

PhD in Microbiology (1994), Columbia University, USA

Research Focus/Interests

Immunology
Infectious Diseases and Autoimmunity

Email: lam_kong_peng@bti.a-star.edu.sg

EXPERIMENT, DISCOVER AND INNOVATE
The immunology group is positioned upstream of BTI's spectrum of R&D activities and complements existing capabilities by providing expertise in molecular and cellular immunological techniques and assays, developing mouse models of autoimmune and inflammatory diseases and identifying targets for downstream development with the aim of discovering biomolecules that have potential applications in human healthcare.

The group has three major research directions. The first is studying the terminal differentiation of B cell with special emphasis on memory B cells and long-lived plasma cells. We focus on deciphering the regulatory functions of microRNAs and signalling molecules in B cell differentiation, and aim to identify new targets for modulating the antibody response. This has a direct impact on the development of novel therapeutic strategies for the modulation of autoantibody production in autoimmune diseases and in the treatment of B cell-derived cancers.

The second area of research is to investigate the immunoregulatory function of natural killer T (NKT) cells in normal immune and autoimmune settings. As these cells uniquely respond to lipid antigens, we aim to discover lipid candidates which could modulate their responses to infection or autoimmunity with the view to develop these lipids as potential vaccine adjuvants.

Last but not least, our third area of research is to understand signal transduction mechanisms in innate immunity focussing on the sensing of pathogenic nucleic acids. In particular, we are interested in studying how molecules such as kinases, helicases and adaptor proteins function in innate immunity against infectious diseases. This could yield novel molecular targets that are amenable for the development of therapeutic drugs such as those that could either enhance the host antimicrobial response or prevent exaggerated host inflammatory response.

immunology_pic

BIRGIT LANE

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BIRGIT LANE

Email: birgit.lane@sris.a-star.edu.sg

As IMB's first Executive Director, Birgit Lane oversaw the Institute's creation in 2007 from her previous position as Executive Director of its forerunner, the Centre for Molecular Medicine. She first joined CMM on coming to Singapore in January 2005, on sabbatical leave from the University of Dundee. Previously she held the Cox Chair of Anatomy and Cell Biology in the College of Life Sciences at Dundee from 1991 until her resignation in 2009. Birgit began her interests in epithelial biology with her BSc and PhD degrees in Zoology at University College London; she worked as a postdoctoral scientist at UCL, Imperial College London and Cold Spring Harbor Laboratory, New York before joining ICRF (now Cancer Research UK) in 1980, where she subsequently became a tenured staff member. In 1990 she moved her group from ICRF Clare Hall to the University of Dundee, to establish the CRUK Laboratories at Dundee, together with her husband David Lane and also David Glover.

Birgit Lane has published over 200 research papers and reviews. She is known internationally for her work on keratins and has a long-standing interest in the function of the keratin cytoskeleton in epithelia and its importance in disease. She has made pioneering contributions to the use of monoclonal antibodies to keratins in diagnostic pathology and cell biology, and to the recognition of keratin mutations as causing inherited skin fragility disorders.

In Singapore, Professor Birgit Lane also holds adjunct appointments in A*STAR's IMCB and in the Departments of Pathology and Biochemistry at NUS, and is an Honorary Visiting Consultant at the National Skin Centre. She also is an Adjunct Professor at the Karolinska Institute, Sweden and Emeritus Professor at the University of Dundee. She is an elected Fellow of the Royal Society of Edinburgh and of the UK's Academy of Medical Sciences.

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David LANE

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David LANE

The p53 lab is focusing on the development of new therapies, new diagnostics and new discoveries in the p53 pathway. 11 Million people living with cancer have specific mutations in the p53 gene leading to the production of a faulty p53 protein. This is half the cases of human cancer. In those that have an apparently normal p53 gene we believe that there are faults in the p53 pathway. We are using a variety of approaches to translate this extraordinary finding into clinical benefit. We work closely with many other groups both in Singapore and in the rest of the world to acheive this. We are using biochemical, biophysical, cell biological and genetic approaches in our work and offer an outstanding international training environment.

News

2019

July - p53 Lab is featured on cover of Cancer Research
Sept - 6th Antibody Symposium - Antibody Engineering The Next Wave

Upcoming Conferences (2019)

12-13 Dec: Peptides and Proteins Society Singapore (P2S2) Symposium 2019

Current Publications

Abdel-Fatah, Broom RJ, Lu J, Moseley PM, Huang B, Li L, Liu S, Chen L, Ma RZ, Cao W, Wang X, Li Y, Perry JK, Aleskandarany M, Nolan CC, Rakha EA, Lobie PE, Chan SYT, Ellis IO, Hwang LA, Lane DP, Green AR, Liu DX,19 (2019). SHON expression predicts response and relapse risk of breast cancer patients after anthracycline-based combination chemotherapy or tamoxifen treatment (2019). B J Cancer, 120(7), 728-745.
Ng S, Juang YC, Chandramohan A, Kaan HYK, Sadruddin A, Yuen TY, Ferrer FJ, Lee XEC, Xi L, Johannes CW, Brown CJ, Kannan S, Aronica PG, Berglund N, Verma CS, Liu LJ, Stoeck A, Sawyer TK, Partridge AW, Lane DP (2019). De-risking drug discovery of intracellular targeting peptides: screening strategies to eliminate false-positive hits. BioRXiv, doi: http://dx.doi.org/10.1101/636563.
Pradhan MR, Siau JW, Kannan S, Nguyen MN, Ouaray Z, Kwoh CK, Lane DP, Ghadessy F, Verma CS (2019). Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket. Nucleic Acids Research, 47(4), 1637–1652.
Xue Y, Barker N, Hoon S, He P, Thakur T, Abdeen SR, Maruthappan P, Ghadessy FJ, Lane DP (2019). Bortezomib Stabilizes and Activates p53 in Proliferative Compartments of both Normal and Tumor Tissues In Vivo. Cancer Res, 79(14), 3595-3607.
Partridge AW, Kaan HYK, Juang YC, Sadruddin A, Lim S, Brown CJ, Ng S, Thean D, Ferrer F, Johannes C, Yuen TY, Kannan S, Aronica P, Tan YS, Pradhan MR, Verma CS, Hochman J, Chen S, Wan H, Ha S, Sherborne B2, Lane DP, Sawyer TK (2019). Incorporation of putative helix-breaking amino acids in the design of novel stapled peptides: Exploring biophysical and cellular permeability properties. Molecules, 24(12).
Koh XY, Koh XH, Hwang LA, Ferrer FJ, Rahmat SAB, Lama D, Lane DP (2019). Therapeutic anti-cancer activity of antibodies targeting sulfhydryl bond constrained epitopes on unglycosylated RON receptor tyrosine kinase . Oncogene. doi: 10.1038/s41388-019-0946-8. [Epub ahead of print].
Ong JFM, Goh HC, Lim SC, Pang LM, Chin JSF, Tan KS, Liang ZX, Yang L, Glukhov E, Gerwick WH, Tan LT (2019). Integrated Genomic and Metabolomic Approach to the Discovery of Potential Anti-Quorum Sensing Natural Products from Microbes Associated with Marine Samples from Singapore. Mar Drugs, 17(1), 72.
Sana B, Chee SMQ, Wongsantichon J, Raghavan S, Robinson RC, Ghadessy FJ (2019). Development and structural characterization of an engineered multi-copper oxidase reporter of protein-protein interactions. J Biol Chem, 294(17), 7002-7012. doi: 10.1074/jbc.RA118.007141. Epub 2019 Feb 15.
Yuen TY, Brown CJ, Xue Y, Tan YS, Ferrer Gago FJ, Lee XE, Neo JY, Thean D, Kaan HYK, Partridge AW, Verma CS, Lane DP, Johannes CW (2019). Stereoisomerism of stapled peptide inhibitors of the p53-Mdm2 interaction: an assessment of synthetic strategies and activity profiles. Chem Sci, 10(26).
Yuri Frosi, Rachael Usher, Dawn Thean Gek Lian, David P. Lane, Christopher J. Brown (2019). Monitoring flux in signaling pathways through measurements of 4EBP1-mediated eIF4F Complex assembly. BMC Biology, 17(1).
Lama D, Liberatore AM, Frosi Y, Nakhle J, Tsomaia N, Bashir T, Lane DP, Brown CJ, Verma CS, Auvin, S. (2019). Structural insights reveal arecognition feature for tailoring hydrocarbon stapled-peptides againstthe eukaryotic translation initiation factor 4E protein. S. Chem Sci., 10(8), 2489-2500.

Colin STEWART

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Colin STEWART

Email: colin.stewart@imb.a-star.edu.sg

Colin Stewart, has been a pioneer in developing many of the techniques that are now widely used in mouse experimental genetics, in establishing protocols for deriving embryonic stem (ES) lines, uniparental ES lines, and for the derivation of the first human ES lines. He was instrumental in identifying the cytokine LIF as being crucial to sustaining stem cell pluripotency (Nature 1988). Subsequently he showed that LIF and its signalling pathway is critical to regulating uterine receptivity for embryo implantation in mammals (Nature 1993). He developed numerous mouse models of congenital diseases, particularly those arising from defective genomic imprinting e.g. Prader-Willi. Over the last decade his interests have centered on the laminopathies, a heterogeneous collection of diseases all arising from mutations in the LaminA gene. He collaborated with Nicolas Lévy, in being the first to show that mutations in the LMNA gene cause progeria (Science 2003), and to make mouse models of many of the laminopathies, including progeria. He also developed the first iPSCs lines derived from patient fibroblasts in establishing an in vitro model for Progeria (HGPS). Currently, he is a founding partner of Daedalus Therapeutics that is developing new treatments to ameliorate cardiomyopathies and vascular disease.

Andrew Nguan Soon TAN

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Tan Nguan Soon, Andrew
Associate Professor

Office: 02s-60
Telephone: 6316 2941
Email: NSTan@ntu.edu.sg

EDUCATION

B.Sc., B.Sc (Hon), Ph.D National University of Singapore

PROFESSIONAL EXPERIENCE

Lee Kong Chian School of Medicine, NTU (2016-now)

Adjunct-PI, Institute of Molecular and Cell Biology, A*STAR (2016-now)

Joint Scientist, KK Women's and Children's Hospital, SingHealth (2013-now)

Joint-SPI, Institute of Molecular and Cell Biology, A*STAR(2012-2016)

RESEARCH INTEREST

Wound Repair

Poor healing wounds represent a silent epidemic that affects a large fraction of the world population and carries a heavy socioeconomic burden. Despite the enormous impact of these poor-healing wounds, effective therapies remain lacking. Effective management of these problems will require better understanding of the healing process to allow the creation of a salubrious environment conducive to healing.

Over the past decade, our lab has worked extensively to understand the transcriptional regulation of skin wound healing and particularly the interplay among different cell types during wound healing. In wound keratinocytes, we showed that nuclear receptor PPARβ/δ inhibits keratinocyte apoptosis at wound edges to maintain a sufficient number of viable wound keratinocytes for re-epithelialization. In fibroblasts, PPARβ/δ controls IL-1 signaling and thereby contributes to the homeostatic control of keratinocyte proliferation. Experimental animal studies showed that the controlled release of PPARβ/δ agonist improves diabetic wound healing through redox modulation of wound microenvironment. We also identified ANGPTL4, a PPAR target gene, as a novel matricellular protein that is essential for proper wound healing. Hyperproliferative wound keratinocytes secrete high amount of ANGPTL4 which plays a major role in cell-cell communication, and cell-matrix interactions during wound healing The ANGPTL4 modulates cell adhesion, migration (movie), differentiation and angiogenesis to facilitate wound closure. We showed that wound healing in ANGPTL4-knockout mice are delayed and share many characteristics of poor healing wounds, including increased/prolonged inflammation, impaired wound-related angiogenesis and ruined extracellular matrix. A cardinal feature of poor healing wounds is a persistent inflammatory response at the wound site. Thus, our future studies will investigate the role of immune-associated reactive oxygen species on wound healing, particularly on tissue remodeling, scar formation and fibrosis. We will develop various mutant mice as physiologically more relevant model for wound healing and fibrosis.

TARGETING METASTASIS
Metastasis accounts for more than 90% of cancer mortality. Once metastasis occurs, surgical excision of the primary tumor no longer guarantees disease free survival and the probability of cancer relapse in distal organs increases significantly. Although most cancer deaths are the result of metastases, cancer research has mainly focused on the primary tumor. In recent years, reactive oxygen species (ROS) which are by-products of aberrant cancer cell metabolism and mitochondrial defect have come to the forefront as potent modifiers of cancer cell behavior. However, very little is known about the precise involvement of ROS in metastatic spread. Over the past decade, my lab has actively interrogated the molecular changes in tumor epithelia at various critical points during tumor metastasis.

Copyright belongs to A/P Andrew Tan Nguan Soon

Our findings have established several paradigms in oxidative stress-driven metastasis. We revealed that non-canonical TGFβ pathways involving TAK1 was a crucial mediator of epithelial-mesenchymal transition. The loss of TAK1 accelerated EMT of cancer cells via an integrin:Rac-induced ROS mechanism. We found that many metastatic tumors upregulated their expression of the matricellular protein, angiopoietin-like 4 (ANGPTL4). This has significant consequences on metastatic escape from the primary tumor as well as extravasation for the formation of secondary micrometastases. Subsequently, our interest on how cancer cells survived in the circulation led to our discovery of an ANGPTL4-Nox1-ROS axis responsible for conferring anoikis resistance. ANGPTL4 also stimulated STAT3-mediated inducible nitric oxide synthase expression and enhanced angiogenesis. Thus, ANGPTL4 is an important redox player in metastasis and a potential therapeutic target. Our lab has developed a neutralizing monoclonal antibody against ANGPTL4 that displays potent in vivo anticancer effects. These findings underscore the role of ROS in multiple events during metastasis and highlight redox therapeutics as a potential adjunctive treatment to existing anticancer regiments. Our future studies will incorporate the effects of ROS on field cancerization and the seed-soil concept into the global view of metastasis. We seek to address how a radial spread of ROS impacts the adjacent normal epithelia and native stroma. Another question we seek to answer is how secondary micrometastases enact field cancerization to corrupt the new "soil". This will provide us with a holistic understanding of how cancer cells leverage on ROS to develop a niche that acts as a "springboard" to EMT and escape from the primary tumor.

Adjunct PIs

Melissa FULLWOOD

Albert CHEN

Jianzhu CHEN

Vincent CHOW

Research Interest

Representative Publications

FU Xin-Yuan

Affiliations

Education

Professional Experience

Research Interest

Selected Publications

Kong Peng LAM

BIRGIT LANE

David LANE

Colin STEWART

Andrew Nguan Soon TAN

EDUCATION

PROFESSIONAL EXPERIENCE

RESEARCH INTEREST

A*STAR celebrates International Women's Day