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Principal investigator

Students	Staff
Caroline McCulloch (PhD Student) Kristopher Montrose (PhD Student) Glenn Bell (MSc Student) Ruhan Jiang (MSc Student) Gary D'Souza (MSc Student)	Kevin (Xueying) Sun (Senior Research Fellow) Shiva Reddy (Senior Research Fellow)  Yih Chih Chan (Research Fellow) Qi Chen (Research Fellow) Yi Yang (Technician)  Aneta Przepiorski(Technician and MSc Student) Swapna Gannabathula (Technician)

 Funding

• Foundation for Research Science and Technology
• Fonterra
• Broad Foundation USA
• Marsden Fund

Research

Our projects are centred around understanding and/or finding treatments for a variety of inflammatory diseases, including cancer. Both academic and commercial work is being undertaken. The laboratory was one of five Auckland, and Otago University laboratories that founded the consortium Lactopharma in 2002, together with the commercial partner Fonterra. Lactopharma seeks to identify bioactives in the dairy industry that can be used to treat an array of major human diseases. A grant from the Broad Foundation, USA, funds work to search for new susceptibility genes for inflammatory bowel disease, to characterize the incidence of NOD2 mutations in the Auckland Crohn's patient population, to understand the biology of NOD2, and to devise a new approach to treat IBD. Funding from the Marsden Fund seeks to unravel a unique mechanism we have discovered that controls the homeostasis of the immune response.

Research areas

• Commercial venture: Lactopharma
• Inflammatory bowel disease
• Leukocyte adhesion
• Cancer therapy

Lactopharma

Milk is highly diversified source of biologically active compounds designed in nature not only for nutrition but to provide growth and other protective factors beneficial for human health and wellbeing. LactoPharma has access to New Zealand's abundant supply of premium cows milk, and supported by commercially focused science teams, has embarked on an exciting bioactives discovery venture. LactoPharma aims to become a global leader in the discovery of commercially exploitable milk bioactives for human health. LactoPharma will focus on bioactive dicovery research to support the development of functional food ingredients, health supplements and pharmaceuticals. These discoveries will allow the development of products useful in the prevention and management of conditions such as osteoporosis, infectious diseases and various inflammatory disorders, including asthma, inflammatory bowel disease, and atherosclerosis.

 

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Understanding the role of Nod2 in inflammatory bowel disease

Crohn's disease (CD) is a chronic inflammatory bowel disease affecting ~1 in 500 people in western countries. The immune system attacks the digestive tract, causing abdominal pain, cramping, diarrhea, rectal bleeding, fever and weight loss. The prevailing theory is that the immune system in genetically susceptible individuals responds incorrectly to intestinal bacteria or viruses. Recent research identified a gene, the NOD2 gene, that was damaged in up to 50% of Crohn's patients. The NOD2 protein that is made from the NOD2 gene helps our immune systems recognise and respond to bacteria, but the damaged NOD2 protein cannot do this correctly in CD patients. We are investigating additional Crohn's susceptibility genes, and are exploring the biology of NOD2. We have discovered a novel pathway by which the expression and function of NOD2 is regulated. The project will allow us to better understand the basis of Crohn's disease, and could lead to a new tool to diagnose disease susceptibility.

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Understanding how the adhesion of white blood cells (leukocytes) is regulated

White blood cells (leukocytes) constantly flow through blood vessels during their role in immunosurveillance, but rapidly stick to vessel walls following infection or injury to gain access to damaged tissues. By an enigmatic process that is absolutely critical for controlling an otherwise rampant immune response, cells gradually lose their "stickiness". We have uncovered the process by which the stickiness of white blood cells is regulated, revealing a fascinating interplay between two signaling molecules present within living cells, and an adhesion receptor that sits on the cell-surface and engages adhesion molecules on the walls of blood vessels. We seek to understand these interactions at the molecular level, and to determine whether they control the movement of living cells through tissues. Having mastered the process controlling the stickiness of cells, we will be in a position to treat chronic inflammatory disease.

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Cancer therapy

Survivin, a member of the inhibitor of apoptosis (IAP) family, is detectable in most cancers, where its presence correlates with an unfavourable prognosis. We showed that tumoral surivin expression was dramatically upregulated with increasing tumor size, which correlates with increasing resistance to immunotherapy. Direct gene transfer of either antisense or dominant-negative forms of survivin inhibited the growth of small tumors, and significantly inhibited growth of large tumors. The growth of large tumors was delayed to an even greater extent by targeting survivin in combination with immunotherapy. Survivin-based therapies were characterized by increased tumor cell apoptosis and anti-tumor CTL generation. Thus, combining treatments that target survivin to restore susceptibility to programmed cell death, with immunotherapeutic strategies that harness the power of anti-tumor immunity, should be investigated for the treatment of large immune-resistant tumors. Current efforts focus on determining the anti-apoptotic arsenal of tumors and devising new approaches to therapy.

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Recent relevant publications

1. Sun X, Vale M, Jiang X, Gupta R, Krissansen GW. Antisense HIF-1alpha prevents acquired tumor resistance to angiostatin gene therapy. Cancer Gene Ther 17: 532-40, 2010.
2. Leung E, Kannan N, Krissansen GW, Findlay MP, Baguley BC. MCF-7 breast cancer cells selected for tamoxifen resistance acquire new phenotypes differing in DNA content, phospho-HER2 and PAX2 expression, and rapamycin sensitivity. Cancer Biol Ther 9: 717-24, 2010.
3. Jiang H, Ma Y, Chen X, Pan S, Sun B, Krissansen GW, Sun X. Genistein synergizes with arsenic trioxide to suppress human hepatocellular carcinoma. Cancer Sci 101: 975-83, 2010.
4. Zhou J, Hu L, Cui Z, Jiang X, Wang G, Krissansen GW, Sun X. Interaction of SDF-1alpha and CXCR4 plays an important role in pulmonary cellular infiltration in differentiation syndrome. Int J Hematol 91: 293-302, 2010.
5. Kong R, Sun B, Jiang H, Pan S, Chen H, Wang S, Krissansen GW, Sun X. Downregulation of nuclear factor-kappaB p65 subunit by small interfering RNA synergizes with gemcitabine to inhibit the growth of pancreatic cancer. Cancer Lett 291: 90-8, 2010.
6. Schippers A, Leuker C, Pabst O, Kochut A, Gruber AD, Leung E, Krissansen GW, Wagner N, Müller W. Mucosal addressin cell-adhesion molecule 1 controls plasma-cell localization, migration and function in the small intestine. Gastroenterology 137: 924-33, 2009.
7. Sun X, Jiang H, Jiang X, Tan H, Meng Q, Sun B, Xu R, Krissansen GW. Antisense hypoxia-inducible factor-1alpha augments transcatheter arterial embolization in the treatment of hepatocellular carcinomas in rats. Hum Gene Ther. 20: 314-24, 2009.
8. Bai X, Sun B, Pan S, Jiang H, Wang F, Krissansen GW, Sun X. Down-regulation of hypoxia-inducible factor-1alpha by hyperbaric oxygen attenuates the severity of acute pancreatitis in rats. Pancreas 38: 515-22, 2009.
9. Sun X, Jiang H, Jiang X, Tan H, Meng Q, Sun B, Xu R, Krissansen GW. Downregulating hypoxia-inducible factor 1 alpha augments transcatheter arterial embolization to treat hepatocellular carcinomas in rats. Hum Gene Ther 20 (4): 314-324, 2009.
10. Hong J, Leung E, Fraser A, Krissansen GW. Nucleic acid from salivary cells for non-invasive genotyping of Crohn’s disease patients. Genet Test 12: 587-9, 2008.
11. Kanwar JR, Palmano KP, Sun X, Kanwar RK, Gupta R, Haggarty N, Rowan A, Ram S, Krissansen GW. 'Iron-saturated' lactoferrin is a potent natural adjuvant for augmenting cancer chemotherapy. Immunol Cell Biol. 86: 2772-88, 2008.
12. Kanwar RK, MacGibbon AK, Black PN, Kanwar JR, Rowan, Vale M, and Krissansen GW. Bovine milk fat enriched in conjugated linoleic and vaccenic acids attenuates allergic airway disease in mice. Clin Exp Allergy 38: 208-218, 2008.
13. Liu F, Wang P, Jiang X, Tan G, Qiao H, Jiang H, Krissansen G, Sun X. Antisense hypoxia-inducible factor 1 alpha gene therapy enhances the therapeutic efficacy of doxorubicin to combat hepatocellular carcinomas. Cancer Sci 99: 2055-61, 2008.
14. Hong J, Leung E, Fraser AG, Merriman TR, Vishnu P, Krissansen GW. IL4, IL10, IL16, and TNF polymorphisms in New Zealand Caucasian Crohn's disease patients. Int J Colorectal Dis 23: 335-337, 2008.
15. Li J, Dong X, Xu Z, Jiang X, Jiang H, Krissansen GW, Sun X. Endostatin gene therapy enhances the efficacy of paclitaxel to suppress breast cancers and metastases in mice. J Biomed Sci 15: 99-109, 2008.
16. Bai JZ, Leung E, Holloway H, Krissansen GW. Alternatively spliced forms of the P180 ribosome receptor differ in their ability to induce the proliferation of rough endoplasmic reticulum. Cell Biol Int 32: 473-83, 2008.
17. Krissansen GW, and Danen E. Integrin superfamily. In: Encyclopedia of Life Sciences. John Wiley & Sons, Ltd: Chichester http://www.els.net/ (2007).
18. Krissansen GW, and Danen E. Integrins: Signalling and disease. In: Encyclopedia of Life Sciences. John Wiley & Sons, Ltd: Chichester http://www.els.net/ (2007).
19. Krissansen GW. Emerging health properties of whey proteins and their clinical implications. J Am Coll Nutr 26: 713S-723S, 2007.
20. Hong J, Leung E, Fraser AG, Merriman TR, Vishnu P, Krissansen GW. TLR2, TLR4 and TLR9 polymorphisms and Crohn's disease in a New Zealand Caucasian cohort. J Gastroenterol Hepatol 22: 1760-6, 2007.
21. Liu F, Tan G, Li J, Dong X, Krissansen GW, Sun X. Gene transfer of endostatin enhances the efficacy of doxorubicin to suppress human hepatocellular carcinomas in mice. Cancer Sci 98:1381-7, 2007.
22. Hong J, Leung E, Fraser AG, Merriman TR, Vishnu P, Krissansen GW. Polymorphisms in NFKBIA and ICAM-1 genes in New Zealand Caucasian Crohn's disease patients. J Gastroenterol Hepatol 22: 1666-70, 2007.
23. Li J, Tan H, Dong X, Xu Z, Shi C, Han X, Jiang H, Krissansen GW, Sun X. Antisense integrin alphaV and beta3 gene therapy suppresses subcutaneously implanted hepatocellular carcinomas. Dig Liver Dis 39 :557-65, 2007.
24. Ma L, Luo L, Qiao H, Dong X, Pan S, Jiang H, Krissansen GW, Sun X. Complete eradication of hepatocellular carcinomas by combined vasostatin gene therapy and B7H3-mediated immunotherapy. J Hepatol 46: 98-106, 2007.
25. Leung E, Hong J, Fraser AG, Merriman TR, Vishnu P, Krissansen GW. Colony-stimulating factor-1 receptor gene polymorphisms and Crohn's disease. Int J Colorectal Dis 22: 995-6, 2007.
26.  Leung E, Hong J, Fraser A, Krissansen GW. Splicing of NOD2 (CARD15) RNA transcripts. Mol Immunol 44: 284-94, 2007.
27. Leung E, Hong J, Fraser AG, Merriman TR, Vishnu P, Krissansen GW. Peroxisome proliferator-activated receptor-gamma gene polymorphisms and Crohn's disease. Int J Colorectal Dis 22: 453-4, 2007.
28. Bai JZ, Mon Y, Krissansen GW. Kinectin participates in microtubule-dependent hormone secretion in pancreatic islet beta-cells. Cell Biol Int 30: 885-94, 2006.
29. Krissansen GW, Singh J, Kanwar RK, Chan YC, Leung E, Lehnert KB, Kanwar JR, Yang Y. A pseudosymmetric cell adhesion regulatory domain in the beta7 tail of the integrin alpha4beta7 that interacts with focal adhesion kinase and src. Eur J Immunol 36: 2203-14, 2006.
30. Liu B, Pan S, Dong X, Qiao H, Jiang H, Krissansen GW, Sun X. Opposing effects of arsenic trioxide on hepatocellular carcinomas in mice. Cancer Sci 97: 675-81, 2006.
31. Leung E, Hong J, Fraser A, Merriman T, Krissansen G. PPAR-gamma and Crohn's disease in New Zealand. Gastroenterology 130: 2249-50, 2006.
32. Xu R, Harrison PM, Chen M, Li L, Tsui TY, Fung PC, Cheung PT, Wang G, Li H, Diao Y, Krissansen GW, Xu S, Farzaneh F. Cytoglobin overexpression protects against damage-induced fibrosis. Mol Ther 13: 1093-100, 2006.
33. Leung E, Hong J, Fraser AG, Merriman TR, Vishnu P, Krissansen GW. Polymorphisms in the organic cation transporter genes SLC22A4 and SLC22A5 and Crohn's disease in a New Zealand Caucasian cohort. Immunol Cell Biol. 84: 233-6, 2006.
34. Luo L, Qiao H, Meng F, Dong X, Zhou B, Jiang H, Kanwar JR, Krissansen GW, Sun X. Arsenic trioxide synergizes with B7H3-mediated immunotherapy to eradicate hepatocellular carcinomas. Int J Cancer 118: 1823-30, 2006.
35. Sun X, Liu M, Wei Y, Liu F, Zhi X, Xu R, Krissansen GW. Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1alpha eradicates gliomas. Cancer Gene Ther 13: 428-35, 2006.
36. Leung E, Hong J, Fraser AG, Merriman TR, Vishnu P, Abbott WG, and Krissansen GW. Polymorphisms of CARD15/NOD2 and CD14 genes in New Zealand Crohn’s disease patients. Immunol Cell Biol. 83:498-503, 2005.
37. Sun X, Qiao H, Jiang H, Zhi X, Liu F, Wang J, Liu M, Dong D, Kanwar JR, Xu R, and Krissansen GW. Intramuscular delivery of antiangiogenic genes suppresses secondary metastases after removal of primary tumors. Cancer Gene Ther. 12:35-45, 2005.
38. Sun X, Krissansen GW, Fung PW, Xu S, Shi J, Man K, Fan ST, and Xu R. Anti-angiogenic therapy subsequent to adeno-associated-virus-mediated immunotherapy eradicates lymphomas that disseminate to the liver. Int J Cancer. 113:670-7, 2005.
39. Krissansen, G.W. Integrin beta 7. AfCS-Nature Signaling Gateway. Molecule Pages. Nature Publishing Group, Editors: Bernd Pulverer and Barbara Marte, 2005.

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