Understanding the role of Sgo1 in colorectal cancer

了解 Sgo1 在结直肠癌中的作用

基本信息

批准号：
8304736
负责人：
Hiroshi Y Yamada
金额：
$ 7.4万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8304736
关键词：
Aberrant crypt foci Address Adenocarcinoma Age Aneuploidy Animal Model Antineoplastic Agents Azoxymethane Biological Biological Process Breast Cancer Etiology Cancer Model Carcinogens Cessation of life Chemopreventive Agent Chromosomal Gain Chromosomal Instability Chromosomal Loss Chromosome Cohesion Chromosomes Collection Colon Colon Carcinoma Colonic Neoplasms Colorectal Cancer DNA DNA copy number Defect Development Diet Habits Drug Delivery Systems Environment Environmental Risk Factor Genes Genetic Predisposition to Disease Genome Genomics Histology Human Interleukin-6 Lesion Liver Lung Malignant Neoplasms Measures Microsatellite Instability Mitotic Chromosome Modeling Molecular Mucous Membrane Mus Mutate Mutation Oncogenes PTGS2 gene Pharmaceutical Preparations Play Population Process Proteins Research Role Sampling Smoking System Techniques Testing Therapeutic Time Tissues Transgenic Mice Translational Research Tumor Suppressor Genes Tumor Suppressor Proteins Wild Type Mouse Work adenoma chromosome loss colon carcinogenesis comparative genomic hybridization drug development drug discovery mouse model novel patient population research and development trait tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer remains to be the second most lethal cancer in the US. More than 50,000 people die of it each year. With clear demand, much effort is being made to develop therapeutic and chemopreventive drugs for colon cancer. However, all drugs developed so far have had large non-responsive patient populations for two reasons; (1) "Colon cancer" is a collection of cancers whose cause and aggravating factors differ. A variety of factors including age, environments, smoking habit, diet and certain genetic predispositions play a role in the development, resulting cancers with different molecular causes. A drug targeting a specific cause often fails against cancers with other causes, and (2) Translational research and drug development system depends on animal models, and current line up of animal models does not comprehensively address different cancer causes. Colon cancers with certain type of molecular causes manage to escape from getting targeted in the process of drug discovery and translational efforts. A prevailing biological trait of human colon cancer is high degree of chromosome instability (CIN). 85% of human colon cancers show CIN. It is hypothesized that high CIN accelerates loss of tumor suppressors and/or gain of oncogenes. A major cause for CIN is a defect in chromosome cohesion, a molecular mechanism involved in tethering chromosomes together. Genes involved in chromosome cohesion are frequently mutated in colon cancer. However, animal models involved in chromosome cohesion and CIN have never been used for colon cancer study or for drug development, under- representing the significant biological process in current drug development system. In this study, we will validate Sgo1 haploinsufficient transgenic mice as a new model for colon cancers aggravated by chromosome cohesion defect and high CIN. We will (i) determine role of Sgo1 in colon cancer development, (ii) identify consequences of Sgo1 mutation with histological and protein marker expression analyses, and (iii) test the hypothesis by analyzing chromosome loss or gain specific to Sgo1 mice compared with wild type control with Comparative Genomic Hybridization (CGH) technique in normal-looking colonic mucosal tissue and in colon tumors. Once validated, the model will aid identifying drugs that work for human population so far non- responsive to existing drugs. PUBLIC HEALTH RELEVANCE: We will test and validate novel transgenic mouse model for colon cancer study. The new model represents a common type of mutation in human colon cancer. The model will aid identifying novel class of drugs, chemopreventive and therapeutic, that work for human population so far non-responsive to existing drugs.

描述（由申请人提供）：大肠癌仍然是美国第二大致命的癌症。每年有50,000多人死亡。有了明确的需求，为结肠癌开发治疗和化学预防药物而付出了很多努力。但是，到目前为止，所有制定的药物都有大量的无反应性患者人群，原因有两个。（1）“结肠癌”是癌症的集合，其原因和加剧因素不同。各种因素，包括年龄，环境，吸烟习惯，饮食和某些遗传易感性在发育中起作用，导致癌症具有不同的分子原因。针对特定原因的药物通常会因其他原因与癌症失败，（2）转化研究和药物开发系统取决于动物模型，而动物模型的当前阵容并未全面解决不同的癌症原因。具有某些类型的分子原因的结肠癌设法逃避了在药物发现和翻译工作过程中的目标。人类结肠癌的主要生物学特征是高度的染色体不稳定性（CIN）。 85％的人类结肠癌显示了CIN。假设高CIN会加速抑制肿瘤的损失和/或癌基因的增益。 CIN的主要原因是染色体内聚力的缺陷，这是将染色体绑定在一起的分子机制。在结肠癌中经常突变参与染色体凝聚的基因。但是，涉及染色体凝聚力和CIN的动物模型从未用于结肠癌研究或药物开发，这代表了当前药物开发系统中的重要生物学过程。在这项研究中，我们将验证SGO1单倍体的转基因小鼠，作为因染色体凝聚力缺陷和高CIN加剧结肠癌的新模型。我们将（i）确定SGO1在结肠癌发展中的作用，（ii）通过组织学和蛋白质标志物表达分析确定SGO1突变的后果，（III）通过分析与野生类型的基因组杂交（CGH）技术相比，通过分析SGO1小鼠特异性染色体损失或特异性SGO1小鼠的增益来检验假设。一旦得到验证，该模型将有助于识别迄今为止对现有药物无反应的人群有效的药物。公共卫生相关性：我们将测试并验证新的转基因小鼠模型进行结肠癌研究。新模型代表了人类结肠癌中一种常见的突变类型。该模型将有助于识别新型药物，即化学预防和治疗性，这些药物对目前对现有药物无反应的人群作用。