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Role of the calcium sensing receptor (CaR) in prevention of colonic hyperproliferation


Since sporadic colorectal cancer (CRC) is, to a major part, preventable, attempts at primary prevention are rational, timely, important, and should be a major priority. Calcium was identified as a chemopreventive agent, since higher intake is associated with reduced risk of CRC. Mechanisms by which high calcium intake prevents neoplastic transformation in the colon are still poorly understood. We willevaluate the role of the calcium sensing receptor (CaR) in colon in calcium-dependent regulation of proliferation. CaR transduces variations in extracellular calcium concentration into modulation of signal transduction pathways involved in proliferation and differentiation, and its expression is lost during colon tumourigenesis. We will use the Nuf mouse model, which has an activating mutation of the CaR, and thus constitutes a unique model to study its role. We expect that the colon of Nuf mice will have increased sensitivity to calcium and will show lower expression levels of proliferation markers when receiving low calcium diet, compared with wild type littermates. In parallel we will investigate signal transduction pathways regulated by CaR in colonocytes. Results of this project would represent an important achievement in colon cancer chemoprevention, a disea se that causes a considerable socio-economic burden. Indeed, if the CaR has a central role in mediating the antimitotic effect of calcium, its expression in precancerous lesions or early colon carcinomas might have predictive value for identifying patients responsive to chemoprevention by calcium. The training program of the fellowship will provide the applicant with further qualifications for the development of an independent research career, will give her experience to lead a research group and will provi de contacts for future co-operations. Support of this fellowship would contribute to the promotion of European scientific excellence and would increase proportion of women involved in high quality science.

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