The role of the extracellular calcium-sensing receptor in dietary Ca2+ chemopreve

描述（由申请人提供）：结直肠癌是西方社会癌症死亡的主要原因之一。膳食钙已被证明对人类和小鼠的结肠肿瘤发生具有化学预防作用。虽然有强有力的证据表明，膳食钙减少结肠肿瘤，钙导致化学预防的分子机制是未知的。关于增加膳食钙如何降低结肠肿瘤的风险，有两种假设。一种是钙结合管腔中过量的离子脂质（对结肠有潜在毒性）并使其排出体外。第二种是钙通过G蛋白偶联的细胞外钙敏感受体（CaSR）直接作用于结肠细胞，从而抑制结肠细胞增殖。我们将直接测试这第二个假设，通过比较化学预防作用的高钙饮食氧化偶氮甲烷致癌物诱导的结肠肿瘤发生在140钙敏感受体缺陷和对照小鼠。这些研究的结果将证明在何种程度上CaSR是负责介导膳食钙化学预防作用的特异性分子靶点：这项工作将确定CaSR是否是结肠上皮细胞发育中的新型信号分子，以及CaSR是否与营养钙对消化系统疾病的积极影响有关。此外，该研究将进一步表征获救的CaSR缺陷小鼠，并确定其是否可以进一步用作结直肠癌的新型动物模型。

DESCRIPTION (provided by applicant): Colorectal cancer is one of the main causes of cancer mortality in Western societies. Dietary calcium has been shown to have a chemopreventive effect on colon tumorigenesis in both humans and mice. Although there is strong evidence that dietary calcium decreases colon tumors, the molecular mechanism by which calcium leads to chemoprevention is unknown. There are two hypotheses for how increased dietary calcium lowers the risk of colon tumors. One is that calcium binds excess ionic lipids (which are potentially toxic to colon) in the lumen and causes them to be excreted. The second is that calcium acts directly via the G-protein-coupled extracellular calcium sensing-receptor (CaSR) to decrease colonic cell proliferation. We will test directly this second hypothesis by comparing the chemopreventive effects of a high calcium diet in azoxymethane carcinogen-induced colon tumorigenesis in 140 calcium-sensing receptor deficient and control mice. The findings of these studies will demonstrate to what extent CaSR is a specific molecular target responsible for mediating the effect of dietary calcium chemoprevention: This work will determine whether or not CaSR is a novel signaling molecule in colonic epithelial cell development and whether or not CaSR is related to the positive impact of nutritional calcium on digestive disease. In addition the study will further characterize the rescued CaSR deficient mouse and determine whether it can be further utilized as a novel animal model of colorectal cancer.