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

描述(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。饮食中的钙已被证明对人类和小鼠的结肠癌发生具有化学预防作用。尽管有强有力的证据表明，饮食中的钙可以减少结肠癌，但钙导致化学预防的分子机制尚不清楚。关于增加膳食钙如何降低患结肠癌的风险，有两个假设。其一是钙结合了管腔中多余的离子脂(对结肠有潜在毒性)，并导致它们被排出。第二，钙通过G蛋白偶联的细胞外钙感应受体(CaSR)直接作用于结肠细胞，从而抑制结肠细胞的增殖。我们将通过比较高钙饮食在140只钙感应受体缺陷小鼠和对照组小鼠中对偶氮甲烷致癌物诱导的结肠癌发生的化学预防作用，直接检验第二个假设。这些研究的结果将证明CaSR在多大程度上是介导膳食钙化学预防效果的特定分子靶点：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，这项研究还将进一步鉴定获救的CaSR缺陷小鼠的特征，并确定它是否可以进一步用作结直肠癌的新动物模型。

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.