Inactivation of the Muc2 gene and colorectal cancer

描述（由申请人提供）：本提案利用了我们的 我们开发了一种小鼠模型，其中我们靶向了Muc 2基因， 编码主要的结肠粘蛋白，用于失活。Muc 2-/-小鼠， 可存活和可繁殖的，不发育可识别的杯状细胞， 肠粘膜的组织病理学改变。到六个月大的时候， Muc 2-/-动物在胃肠道中发生发育异常和癌， 包括直肠，这是Apc小鼠中不形成肿瘤的部位 突变这一点特别重要，因为没有其他啮齿动物 人直肠癌模型，临床上和 在生物学上不同于结肠癌。 Muc 2-/-小鼠的开发是我们广泛工作的下一步， 人和小鼠MUC 2基因的结构和功能分析， 观察到人类和化学上存在粘蛋白产生的损失， 诱发的啮齿类动物异常隐窝病灶（ACF）， 结肠肿瘤的发展，其特征是代表性不足 杯状细胞最重要的是，ACF的发展先于肿瘤的形成 在Apc 1638小鼠中，其携带遗传失活的Apc等位基因。 因此，Muc 2-/-小鼠中的肿瘤发展强烈支持以下假设 粘蛋白产生和杯状细胞表型的损失是足够的， 可能是肠道肿瘤形成的必要早期步骤， 特别是导致直肠癌 在本申请中，我们将：1）表征分子生物学， Muc 2-/-小鼠的表型，通过确定有助于 Muc 2-/-小鼠肠细胞成熟的破坏，以及 补偿机制是针对不同的水平和地点， 其它粘蛋白基因和肠三叶因子（ITF）的表达， 在杯状细胞中特异性表达。2)确定是否以及如何 Muc 2基因的遗传损伤与肿瘤的Apc通路有关 通过研究Apc的突变或Apc的改变， 在肿瘤发展中是必须的，或者在肿瘤发生中是否存在突变。 替代途径（即cdx 2）参与Muc 2-/- 老鼠. 3)通过利用已经可用的小鼠模型（Apcl 638和ITF-/- 动物），我们将直接测试是否有损失之间的相互作用， Muc 2和Apc突变，以及Muc 2主要产物的缺失在Apc中的作用 杯状细胞（Muc 2和ITF）在肿瘤发生中的作用。

DESCRIPTION (provided by applicant): This proposal capitalizes on our development of a mouse model in which we have targeted the Muc2 gene which encodes the major colonic mucin, forinactivation. The Muc2-/- mice, which are viable and fertile, do not develop recognizable goblet cells, and the histopathology of the intestinal mucosa is distorted. By six months of age the Muc2-/-animals develop dysplasia and carcinoma in the gastrointestinal tract, including the rectum, a site at which tumors do not form in mice with Apc mutations. This is of particular importance since there exists no other rodent model of human rectal cancer, a major site of cancer that is clinically and biologically distinct from colon cancer. The development of the Muc2-/- mouse is the next step of our extensive work on the structural and functional analysis of the human and mouse MUC2 genes and on the observation that there is loss of mucin production in human, and chemically induced rodent aberrant crypt foci (ACF), early morphological lesions in the development of colon tumors, which are characterized by under-representation of goblet cells. Most important, the development of ACF precedes tumor formation in the Apc 1638 mouse, which carries a genetically inactivated Apc allele. Thus, tumor development in the Muc2-/- mouse strongly supports the hypothesis that loss of mucin production and the goblet cell phenotype is a sufficient, and perhaps a necessary early step for intestinal tumor formation and may specifically lead to rectal cancer. In this application, we will: 1) characterize the molecular biology and phenotype of the Muc2-/- mouse by determining the mechanisms contributing to the disruption of intestinal cell maturation in the Muc2-/- mouse, and whether compensatory mechanisms take place regarding levels and location of the expression of other mucin genes and intestinal trefoil factor (ITF), specifically expressed in goblet cells. 2) determine whether and how the genetic lesion in the Muc2 gene is related to the Apc pathway of tumor formation by investigating whether mutations in Apc, or alterations of the Apc pathway, are obligatory in tumor development, or whether mutations in alternative pathways (i.e. cdx2) are involved in tumor formation in the Muc2-/- mouse. 3) by utilizing mouse models already available (Apcl 638 and ITF-/- animals), we will directly test whether there is interaction between loss of Muc2 and mutation in Apc, and the role that absence of the major products of goblet cells (Muc2 and ITF) has in tumor development.