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Dr Lee Parry  -  PhD


Primary Research

In recent years the importance of diet and dysbiosis of gut microbiota in driving these inflammatory loops has been recognised.  The interaction between dietary intake and the microbiota has been well studied, which has led to the prediction of a driver-passenger model, where CRC can be initiated by “driver” bacteria which are eventually replaced by “passenger“ bacteria3. Intensive work in recent years using mouse models has led to the identification of genes and mechanisms that link changes in the microbiota to DNA methylation, inflammation and cancer.  It is DNA methylation which links these factors together as it is a process which links the environment to phenotype altering DNA modifications. Hyper-methylated DNA in the promoter of a gene is recognised by members of the methyl binding protein (MBP) family which recruit transcriptional silencing machinery.  Thus these proteins can act as master controllers, by silencing the genes that are correctly methylated  or alternatively silencing genes aberrantly methylated by disease processes 4. My primary research focuses on these MBPs as they regulate genes which play a role in determining immune/inflammatory responses  (e.g. IL-4, Ifng & FoxP3) and we have demonstrated that in Apcmin/+ mice the deficiency of MBPs Mbd2 or Kaiso can suppress intestinal tumourigenesis5.  We are investigating the genes and pathways that these MBPs regulate in the intestinal stem cell and immune cells in altered microbiotic, inflammatory and disease environments.  Understanding these mechanisms may allow us to manipulate MBPs to shift responses in disease towards relieving immunosuppression and driving antitumor immunity that, when combined with other therapies, may ultimately result in tumour cell clearance 6-8.

References

  1. C. R. UK, Cancer worldwide - Common Cancers, http://www.cancerresearchuk.org/cancer-info/cancerstats/
  2. L. M. Coussens, L. Zitvogel and A. K. Palucka, Science, 2013, 339:286-291
  3. H. Tjalsma, A. Boleij, J. R. Marchesi and B. E. Dutilh, Nat Rev Microbiol, 2012, 10:575-582
  4. L. Parry and A. R. Clarke, Genes Cancer, 2011, 2:618-630
  5. O. J. Sansom, J. Berger, S. M. Bishop, B. Hendrich, A. Bird and A. R. Clarke, Nat Genet, 2003, 34:145-147
  6. M. Har-Noy, in Oncology News, ed. R. Or, Online, 2009, pp. 110-112
  7. M. Yamamoto, T. Kamigaki, K. Yamashita, Y. Hori, H. Hasegawa, D. Kuroda, H. Moriyama, M. Nagata, Y. Ku and Y. Kuroda, Oncol Rep, 2009, 22:337-343
  8. M. Tosolini, A. Kirilovsky, B. Mlecnik, T. Fredriksen, S. Mauger, G. Bindea, A. Berger, P. Bruneval, W. H. Fridman, F. Pagès and J. Galon, Cancer Res, 2011, 71:1263-1271