Supervisor View Full Details 2nd

• genetics, genomics and molecular biology
• infectious disease and the immune system
• cell and developmental biology/regenerative medicine
• physiology and non-communicable disease
• cancer/oncology

• Medicine
• Surgery

• Gastroenterology
• Infectious diseases
• Immunology
• Oncology

Research Interests:
Host-Microbe Interaction, Inflammation, and Cancer Biology
(1) Host-Microbe interactions in health and inflammatory disease
(2) Immunopathology in inflammatory disease and cancer
(3) Mechanisms underpinning cross-talk and synergism between inflammatory signalling pathways
(4) Specific focus on Interferon (IFN) and Tumor Necrosis Factor (TNF) signalling pathways
(5) Crosstalk between inflammatory and oncogenic signalling pathways
(6) Epigenetic mechanisms underpinning regulation of inflammatory, anti-viral and oncogenic gene expression
(7) Functional genomics analysis of inflammatory, cell survival and cell death pathways
(8) Discovery of cancer cell intrinsic tumour suppressor mechanisms underpinning immune-mediated suppression of cancer

My group's research interests are in the areas of Host-Microbe Interaction, Inflammation and Cancer Biology. Our group is exploring the molecular and cellular mechanisms underpinning the role of the immune system in host recognition of microbes, chronic inflammatory diseases such as Inflammatory Bowel Disease (IBD), type I diabetes and colon cancer. In terms of IBD and colon cancer, our research group is particularly interested in how the relative sensitivity and resistance of intestinal epithelial cells and colon cancer cells to immune-mediated apoptosis contributes to disease pathogenesis and response to therapeutic interventions. The molecular mechanisms - signal transduction, transcriptional regulation and epigenetic - underpinning the regulation of gene expression in response to inflammatory stimuli in immune, non-immune cells and cancer cells and how this contributes to disease pathogenesis is the main focus of our research. Specifically, they have an interest in understanding how the synergistic interactions between IFN-gamma and other inflammatory stimuli such as TNF-alpha both in terms of their overall effect on inflammatory gene expression and also cell fate decisions contribute to pathogenesis in diseases such as IBD, type I diabetes and other inflammatory conditions.

It is well appreciated that in IBD and type I diabetes, pro-inflammatory cytokines (IFN-gamma and TNF-alpha) induce the death of epithelial cells thereby compromising the function of the gut and the pancreas respectively. Currently, in the context of collaborations with academic and pharmaceutical groups we are investigating the possible roles of signalling pathways and epigenetic modifiers in regulating inflammatory gene expression and cell fate decisions in response to these and other stimuli.

We use a combination of in vitro cell and molecular biology based approaches, functional genomics approaches, in vivo based animal models of inflammation, inflammation linked colon cancer, human biopsy tissue and primary cultures of human organoids 'mini-guts' to investigate basic mechanisms of disease with a focus on inflammatory bowel disease. In addition they use these various systems for drug target identification, drug target validation studies and for pre-clinical profiling of novel drug candidates for efficacy in the setting of chronic intestinal inflammation. They also have ongoing active research projects in the areas of host microbe interactions with a particular interest in the mechanisms underpinning interaction of host cells with gut commensal bacteria.

Description of project: The two major forms of Inflammatory Bowel Disease (IBD), Crohn's disease (CD) and Ulcerative colitis (UC), are chronic relapsing inflammatory diseases of the gut that usually present in the second or third decade of life and are increasing in incidence. A substantial proportion of patients with IBD achieve sub-optimal or inadequate control of their disease with existing drug treatments, including anti-TNF biologics, which produce sustained remission in only 35-40% of patients. These clinical data suggest that additional unknown and redundant mechanisms not affected by TNF inhibitors alone are contributing to disease progression. Therefore, the potential for new therapies to target these mechanisms by inhibiting more than one inflammatory cytokine simultaneously is an attractive proposition.

We are seeking a highly motivated candidate to join the our Gut Inflammation Research group to identify new inflammatory mediators and investigate the specific signalling, epigenetic and transcriptional mechanisms through which pairs of inflammatory mediators synergise to induce inflammatory gene expression and cell death in intestinal epithelial cell lines and human intestinal organoids 'mini-guts'. The trainee will use these systems to discover and validate novel targets in IBD for the development of innovative medicines. The goal of our group is to identify and validate several new therapeutic targets for patients with IBD, including those patients that do not respond satisfactorily to current therapeutic approaches such as anti-TNF biologics.

The successful candidate will establish and use 3-D and 2-D human intestinal organoid 'mini-gut' culture systems and to study specific epithelial cell functions (i.e. apoptosis, necroapoptosis, cytokine and chemokine production, mucus production, defensin production, barrier function). The candidate will use intestinal epithelial cell lines and organoid cultures to perform various RNAi and phenotypic screens to identify new inflammatory mediators. The person will also investigate the epigenetic and transcriptional mechanisms underpinning synergistic regulation of intestinal epithelial cell inflammatory gene expression using a combination of ChIP-seq, ChIP-qPCR, RNAseq, and qRT-PCR. In this position, the individual is expected to make major scientific laboratory-based contributions to the research goals and milestones of the group and will have the opportunity to interact with gastroenterologists and scientists in a multi-disciplinary team.