Animal model of Gardner's syndrome, a life threatening form of familial cancer

描述（由申请人提供）：在本提案中，我基于一些非常令人兴奋的初步数据，这些数据涉及维生素D受体（VDR）在加德纳综合征（家族性腺瘤性息肉病（FAP）的衍生物）中的作用。FAP是一种常染色体显性遗传疾病，由腺瘤性结肠息肉病（APC）肿瘤抑制基因突变引起，以胃肠道息肉为特征。在一些FAP患者中，那些患有加德纳综合征的患者，发生结肠外病变，包括骨瘤、骨混浊、硬纤维瘤和大的表皮样囊肿。这些结肠外表现使得加德纳综合征在临床上特别难以处理。奇怪的是，APC突变动物模型中没有一个发展出FAP的这些结肠外表现，这表明其他修饰的遗传、表观遗传或环境因素对FAP背景起作用，从而导致人类的加德纳综合征。值得注意的是，当我们将VDR-/-动物与APC 1638 N/+突变动物杂交时，我们观察到在任何亲本菌株中都不存在的大表皮样囊肿的快速发展。这些囊肿在组织学上与加德纳综合征患者的囊肿难以区分。考虑到这些患者中也发生骨缺损，以及VDR与皮肤病变的强相关性，我们假设VDR-/-：APC 1638 N/+小鼠可能代表加德纳综合征的模型。在这个提议中，我提出了旨在直接检查的实验：1。如果在这些动物中也发生加德纳综合征的其他结肠外病变特征，2.维生素D基因通路多态性是否与FAP患者的结肠外病变以及结直肠癌相关。

DESCRIPTION (provided by applicant): In this proposal I build on some very exciting preliminary data regarding a role for the vitamin D receptor (VDR) in Gardner's syndrome, a derivative of familial adenomatous polyposis (FAP). FAP is an autosomal dominant disease caused by a mutation in the adenomatous polyposis coli (APC) tumor suppressor gene and is characterized by gastrointestinal polyps. In some FAP patients, those with Gardner's syndrome, extra-colonic lesions including osteomas, bone opacity, desmoids and large epidermoid cysts occur. These extracolonic manifestations make Gardner's syndrome particularly difficult to manage clinically. Curiously, none of the APC mutant animal models develop these extra-colonic manifestations of FAP indicating that other, modifying genetic, epigenetic or environmental factors work on the FAP background to result in Gardner's Syndrome in the human. Remarkably, when we crossed VDR-/- animals with APC1638N/+ mutant animals we observed the rapid development of large epidermoid cysts that were not present in either of the parental strains. These cysts were histologically indistinguishable from those that occur in patients with Gardner's syndrome. Given that defects in bone also occur in these patients, as well as the strong association of the VDR with skin lesions, we hypothesize that the VDR-/-:APC1638N/+ mouse may represent a model of Gardner's syndrome. In this proposal, I propose experiments designed to directly examine: 1. if the other extra-colonic lesions characteristic of Gardner's syndrome also occur in these animals, 2. how the VDR attenuates Gardner's syndrome, and 3.if the polymorphisms of Vitamin D Gene Pathway are related to the extra-colonic lesions as well as colorectal cancer in FAP patient.