权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
8450746
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 2014-11-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450746
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 Targeting 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.

描述（由申请人提供）：结直肠癌仍然是美国第二大致死性癌症。每年有5万多人死于该病。随着需求的明确，人们正在努力开发结肠癌的治疗和化学预防药物。然而，由于两个原因，迄今为止开发的所有药物都有大量的无反应患者群体;（1）“结肠癌”是一组病因和加重因素不同的癌症。多种因素，包括年龄、环境、吸烟习惯、饮食和某些遗传倾向在癌症的发展中起作用，导致不同分子原因的癌症。针对特定病因的药物往往无法对抗其他病因的癌症，以及（2）转化研究和药物开发系统依赖于动物模型，目前的动物模型系列并不能全面解决不同的癌症病因。具有某些类型的分子原因的结肠癌在药物发现和转化努力的过程中设法逃脱靶向。人类结肠癌的一个普遍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CIN。假设高CIN加速肿瘤抑制因子的丧失和/或癌基因的获得。CIN的一个主要原因是染色体凝聚力的缺陷，这是一种将染色体束缚在一起的分子机制。参与染色体凝聚的基因在结肠癌中经常发生突变。然而，涉及染色体凝聚和CIN的动物模型从未用于结肠癌研究或药物开发，不能代表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Sgo 1单倍不足转基因小鼠作为一种新的模型，结肠癌加重染色体凝聚缺陷和高CIN。我们将（i）确定Sgo 1在结肠癌发展中的作用，（ii）通过组织学和蛋白质标记物表达分析确定Sgo 1突变的后果，以及（iii）通过比较基因组杂交（CGH）技术在正常结肠粘膜组织和结肠肿瘤中分析Sgo 1小鼠与野生型对照相比的染色体丢失或获得来检验假设。一旦得到验证，该模型将有助于确定对人类有效的药物，迄今为止对现有药物无反应。