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Dr Lee Parry  -  PhD


A consistent feature of these MBD deficient models is their impact upon the Wnt pathway, either directly or indirectly. Deletion of either Mbd2 or the related protein Kaiso represses the Wnt pathway and indeed represses tumorigenesis (see figure; Sansom et al; Nat Gen (34), 2003). The genes that are regulated by these MBD proteins can control the key early events of the disease process and represent new potential targets for therapeutic intervention. My primary focus is on taking these MBD regulated genes forward and assessing which are the key ones in terms of their potential to modify stem cell fate and tumorigenesis via:

  • Transcriptome analysis of these strains has identified many novel potential therapeutic candidates for colorectal cancer and also candidate intestinal stem cell markers. I am analysing a selection of these candidate genes to characterize which are direct MBD protein targets and what their roles are in the intestinal epithelium.
  • Transgenic models targeted for some of these MBD proteins are viable and fertile, however MBD2 for example is required for correct spatial gene expression in the gut. Using various agents to insult the intestinal epithelium I am assessing potential effects of universally deregulating MBD target genes via therapeutics.
Figure 1. Deficiency of MBD2 increases lifespan of mice in a dose dependant manner

Figure 1. Deficiency of MBD2 increases lifespan of mice in a dose dependant manner

Figure 1. Sansom et.al (Nat. Gen. 34, 2003)

Other projects:

In keeping with the labs principal interests I also have ongoing work using our other murine transgenic models:

  • Activation of K-ras augments the Wnt pathway, this enables a more rapid analysis of the roles of Wnt target genes in tumourigenesis. Our models are allowing me to investigate the relevance of immediate Wnt target genes in other organs such as kidney and liver.
  • Selectively deleting Wnt pathway genes and targets using Cre-Lox technology is allowing us to investigate the importance of genes with key roles in early tumourigenesis to assess their relevance as therapeutic targets in established tumours.