Bone Morphogenetic Protein signalling and stromal-epithelial interaction in intestinal inflammation and carcinogenesis. (360G-Wellcome-206314_Z_17_Z)

£1,792,405

The intestinal mucosa is a complex ecosystem and the epithelium has a dynamic relationship with underlying stroma. Key aspects of intestinal homeostasis and disease states, including inflammatory bowel disease and cancer are characterized by the interdependence of the epithelial and stromal compartments. Inter-compartmental cell-signalling pathways regulate intestinal epithelial cell fate determination in homeostasis, and transient perturbation of these networks is required in the physiological response to inflammation and injury. This promotes epithelial stem cell behaviour, cell proliferation and migration as part of a wound healing response. However, failure of restoration of homeostatic control in chronic inflammation, or pathological disruption of signalling can result in neoplasia initiation and progression. In resultant tumours, optimally selected somatic mutation spectra differ and reflect these variable influences on lesion pathogenesis. This proposal will explore these concepts using disruption in Bone Morphogenetic Protein signalling and it's pleiotrophic antagonist Gremlin1, as exemplars of the paradigm. Specific goals include: 1. Identifying stromal cell populations expressing Grem1 in intestinal regeneration and tumour desmoplasia. 2. Assess the functional role of BMP disruption in these conditions. 3. Using mouse models to test therapeutic manipulation of BMP signalling. 4. Using somatic mutation analysis to generate molecular biomarkers of Grem1 initiated tumourigenesis.

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Grant Details

Amount Awarded 1792405
Applicant Surname Leedham
Approval Committee Science Interview Panel
Award Date 2017-04-05T00:00:00+00:00
Financial Year 2016/17
Grant Programme: Title Senior Research Fellowship Clinical
Internal ID 206314/Z/17/Z
Lead Applicant Prof Simon Leedham
Partnership Value 1792405
Planned Dates: End Date 2023-07-01T00:00:00+00:00
Planned Dates: Start Date 2018-01-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East
Sponsor(s) Prof Christopher Conlon, Prof Peter Donnelly