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

加德纳综合征的动物模型，一种危及生命的家族性癌症

• 批准号: 8243096
• 负责人: Yong-Sik Bong
• 金额: $ 16.87万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-04 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243096
• 关键词: Adenomatous Polyposis Coli; Age; Aggressive Fibromatosis; Alopecia; Animal Model; Animals; Attenuated; Binding; Calcium; Cells; Characteristics; Cholecalciferol; Colon Carcinoma; Colorectal Cancer; Coupled; Cyst; Data; Defect; Development; Disease; Early identification; Early treatment; Environmental Risk Factor; Epidemiologic Studies; Epigenetic Process; Epithelial cyst; Exhibits; Face; Gardner' s Syndrome; Gastrointestinal Polyp; Genes; Genetic; Genetic Polymorphism; Growth; Hair follicle structure; Hereditary Malignant Neoplasm; Histologic; Homeostasis; Human; Intervention; Lesion; Life; Ligand Binding; Ligands; Limb structure; Malignant Neoplasms; Mediating; Metabolism; Modeling; Mus; Mutation; Osteoma; Pathway interactions; Patients; Phenotype; Plasma; Play; Polyps; Process; Quality of life; Reporting; Role; Scalp structure; Site; Syndrome; Transcript; Transcriptional Activation; Tumor Suppressor Genes; Variant; Vitamin D; Vitamin D-Binding Protein; Vitamin D3 Receptor; Work; bone; cancer cell; cancer risk; design; fibroma; high risk; mutant; outcome forecast; receptor expression; receptor function; repository; research study; skin lesion; uptake

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. PUBLIC HEALTH RELEVANCE: Gardner's syndrome is a variant of FAP, which has a variety of extra-colonic manifestations such as fibroma, osteoma, and most characteristically large epidermoid cysts. Epidermal cysts are the most common skin lesions of Gardner's syndrome, typically occurring at an earlier age and at multiple sites, including the face, scalp, and extremities. Due to the poor quality of life and the rapid development of polyps to colorectal cancer, Gardner's syndrome is actually considered a severe life threatening disease. Consequently, early identification and therapy of the disease are critical through the development of appropriate model organisms. Bone defects and multiple skin lesions characterize Gardner's syndrome and our preliminary data provides evidence that alterations in vitamin D receptor expression or function coupled with APC mutation may play a role this deadly disease.

描述（由申请人提供）：在本提案中，我建立了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) 的一种衍生物）中的作用。 FAP是一种由腺瘤性结肠息肉病（APC）抑癌基因突变引起的常染色体显性遗传病，以胃肠道息肉为特征。在一些FAP患者中，患有加德纳综合征的患者会出现结肠外病变，包括骨瘤、骨混浊、硬纤维瘤和大表皮样囊肿。这些结肠外表现使得加德纳综合征在临床上特别难以治疗。奇怪的是，没有一个 APC 突变动物模型会出现 FAP 的这些结肠外表现，这表明其他修饰遗传、表观遗传或环境因素对 FAP 背景起作用，导致人类出现加德纳综合症。值得注意的是，当我们将 VDR-/- 动物与 APC1638N/+ 突变动物杂交时，我们观察到大表皮样囊肿的快速发展，而这在任何亲本品系中都不存在。这些囊肿在组织学上与加德纳综合征患者中出现的囊肿无法区分。鉴于这些患者也出现骨缺陷，以及 VDR 与皮肤损伤的密切相关，我们假设 VDR-/-:APC1638N/+ 小鼠可能代表加德纳综合征的模型。在本提案中，我提出了旨在直接检查：1. 加德纳综合征的其他结肠外病变特征是否也发生在这些动物中的实验，2. VDR 如何减轻加德纳综合征，以及 3. 维生素 D 基因通路的多态性是否与 FAP 患者的结肠外病变以及结直肠癌相关。 公共卫生相关性：加德纳综合征是 FAP 的一种变体，具有多种结肠外表现，例如纤维瘤、骨瘤和最典型的大表皮样囊肿。表皮囊肿是加德纳综合征最常见的皮肤病变，通常发生在较早的年龄和多个部位，包括面部、头皮和四肢。由于生活质量差以及息肉迅速发展为结直肠癌，加德纳综合征实际上被认为是一种严重危及生命的疾病。因此，通过开发适当的模式生物来早期识别和治疗该疾病至关重要。加德纳综合征的特点是骨缺损和多处皮肤损伤，我们的初步数据提供了证据，表明维生素 D 受体表达或功能的改变以及 APC 突变可能在这种致命疾病中发挥作用。