Proteomic Validation of the Min Mouse Model of Colon Cancer

结肠癌小鼠模型的蛋白质组学验证

• 批准号: 7215018
• 负责人: ANTHONY T YEUNG
• 金额: $ 8.55万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215018
• 关键词: aging; alleles; biomarker; colon; colon neoplasms; gene mutation; human; model; neoplasm /cancer; proteins; proteomics

DESCRIPTION (provided by applicant): A Familial Adenomatous Polyposis' (FAR) patient has inherited a heterozygous mutation in the tumor suppressor gene APC (adenomatous polyposis coli) and will most likely develop colon cancer in his/her lifetime often because of loss of heterozygosity that inactivates the remaining APC allele. APC function is also lost in over 85% of sporadic colon cancer cases, confirming its causal role in colon cancer. One of several animal models, an Ape heterozygous codon 850 nonsense mutation in the C57BL/6J mice, is Min (multiple intestinal neoplasia) and is characterized by the appearance of benign tumors (polyps) in the small intestine. The strain propagated at the Fox Chase Cancer Center uniquely shows a high incidence of tumors in the colon and in the small intestines, thus representing a model similar to FAR. Our laboratory has completed the first detailed proteomic comparison of apparently-non-neoplastic human FAR colon crypts against crypts from non-mutation carriers, encompassing over 4000 protein species in which over half of the protein species were identified by mass spectrometry. We discovered that the protein profile of the FAR colon crypt is already significantly changed by the heterozygous APC mutation. This finding suggests that when a cell of the normal colon sustains the first APC mutation, it creates a previously unsuspected new cellular environment in which proteomic information may lead to the identification of biomarkers and potential targets for therapy. At least 80% of these human crypt proteins have orthologs in mouse. The Specific Aims are: Aim 1: To produce high resolution proteomic maps of colon crypts from the FCCC Min mice and C57BL/6J control mice and to test whether they correspond to the human counterparts in FAR patients and non-FAP controls; and whether the proteomic differences between APC and control are similar in humans and mice. Aim 2: Age is a major factor in colon cancer. Min mice and C57BL/6J control mice of four age groups will be compared to elucidate the effects of age on the onset of the proteomic changes in the apparently-non-neoplastic colon crypts of the Min mice. We expect that the cross-species validations offered by these experiments will confirm whether Min mice are a valid resource for further biomarker discovery and enable chemoprevention experiments that capitalize on the biomarker changes discovered in the normal colon crypts of FAR patients. Although our laboratory has discovered several new potential biomarkers in the colon that signal early changes towards colon cancer, we need an animal model for testing whether some of these markers can be targeted with cancer prevention drugs. The Min mouse model genetically mimics humans for colon cancer. The proposed work will demonstrate whether it is a perfect model for the human disease.

描述（由申请人提供）： 家族性腺瘤性息肉病（FAR）患者遗传了肿瘤抑制基因APC（腺瘤性结肠息肉病）中的杂合突变，并且在他/她的一生中很可能发展为结肠癌，通常是因为杂合性丢失使剩余的APC等位基因失活。APC功能也在超过85%的散发性结肠癌病例中丢失，证实了其在结肠癌中的因果作用。几种动物模型之一，C57 BL/6 J小鼠中的Ape杂合密码子850无义突变，是Min（多发性肠肿瘤），其特征在于小肠中出现良性肿瘤（息肉）。在Fox Chase癌症中心繁殖的菌株独特地显示结肠和小肠中肿瘤的高发病率，因此代表了与FAR相似的模型。我们的实验室已经完成了第一个详细的蛋白质组学比较明显的非肿瘤性人类FAR结肠隐窝对隐窝从非突变携带者，包括超过4000种蛋白质种类，其中超过一半的蛋白质种类被确定的质谱。我们发现FAR结肠隐窝的蛋白质谱已经被杂合APC突变显著改变。这一发现表明，当正常结肠的细胞维持第一个APC突变时，它创造了一个先前未被怀疑的新细胞环境，其中蛋白质组学信息可能导致生物标志物和潜在治疗靶点的鉴定。这些人隐窝蛋白中至少80%在小鼠中具有直向同源物。具体目标是：目标1：为了产生来自FCCC Min小鼠和C57 BL/6 J对照小鼠的结肠隐窝的高分辨率蛋白质组图谱，并测试它们是否对应于FAR患者和非FAP对照中的人类对应物;以及APC和对照之间的蛋白质组差异在人类和小鼠中是否相似。目的2：年龄是结肠癌的主要因素。将比较四个年龄组的Min小鼠和C57 BL/6 J对照小鼠，以阐明年龄对Min小鼠的明显非肿瘤性结肠隐窝中蛋白质组学变化发生的影响。我们期望这些实验提供的跨物种验证将确认Min小鼠是否是进一步发现生物标志物的有效资源，并使化学预防实验能够利用FAR患者正常结肠隐窝中发现的生物标志物变化。虽然我们的实验室已经在结肠中发现了几种新的潜在生物标志物，这些生物标志物标志着结肠癌的早期变化，但我们需要一种动物模型来测试这些标志物中的一些是否可以用癌症预防药物靶向。Min小鼠模型在遗传上模仿了人类的结肠癌。这项工作将证明它是否是人类疾病的完美模型。