An Integrated Study of Mitochondrial Pathways in Colorectal Cancer

结直肠癌线粒体途径的综合研究

基本信息

批准号：
8891387
负责人：
Myron D Gross
金额：
$ 61.5万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8891387
关键词：
Accounting Address Affect Animals Apoptotic Area Biogenesis Biological Markers Biology Cancer Etiology Carotenoids Cells Cessation of life Chinese People Cohort Studies Colorectal Adenoma Colorectal Cancer Complex Copy Number Polymorphism DNA DNA Damage DNA copy number Development Diet Dietary intake Drug Metabolic Detoxication Environmental Risk Factor Epidemiologic Studies Ethnic Origin Evaluation F2-Isoprostanes Frequencies Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Glutathione Reductase Goals Haplogroup Health Human Incidence Individual Inflammation Investigation Laboratories Large Intestine Carcinoma Lead Leukocytes Life Style Literature Malignant - descriptor Malignant Neoplasms Measurement Measures Mediation Mitochondria Mitochondrial DNA Nested Case-Control Study Nuclear Oxidative Stress Pathogenesis Pathway interactions Plasma Polymerase Chain Reaction Population Positioning Attribute Prevention strategy Production Prospective Studies Public Health Reactive Oxygen Species Research Risk Risk Factors Role Shapes Singapore Solid Neoplasm Source Strategic Planning System Time United States National Institutes of Health Urine antioxidant enzyme base biobank cancer risk catalase cell transformation cohort colon carcinogenesis colorectal cancer prevention fruits and vegetables glutathione peroxidase high risk innovation lifestyle factors mitochondrial dysfunction mitochondrial genome non-genetic novel oxidation oxidative DNA damage oxidative damage peripheral blood population based prospective urinary

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial dysfunction and increased production of reactive oxygen species (ROS) may have a key role in the pathogenesis of several cancers, including colorectal cancer. Extensive studies have shown mitochondria to be the predominant endogenous source of ROS in cells. Increased ROS exposure induces oxidative DNA damage in mitochondrial and nuclear DNA as well as the activation of apoptotic and inflammation pathways. Through these activities, ROS exposure can lead to malignant transformation of cells. The extent of oxidative damage and malignant transformation is influenced by the activity of the ROS detoxification system. Subtle changes in ROS production and detoxification are influenced by environmental factors and genetic variation between individuals. While these activities are well established in cellular and animal studies, few human studies have evaluated the relationship between mitochondrial dysfunction and colorectal cancer risk. We will prospectively evaluate the association between several aspects of mitochondrial dysfunction, genetic variation, oxidative damage and the ROS detoxification system and colorectal cancer in a frequency matched nested case-control study of 640 colorectal cancer cases and 1280 controls within a well-established prospective cohort, the Singapore Chinese Health Study. Indicators of mitochondrial dysfunction include mitochondrial DNA copy number, mitochondria DNA damage as measured by quantitative real time polymerase chain reaction and oxidative damage as measured by urinary F2-isoprostanes and plasma fluorescent oxidation products. The mitochondrial genome and nuclear genes related to mitochondrial biogenesis will be evaluated for genetic susceptibility to oxidative stress through the measurement of polymorphisms and haplogroups. Additional major determinants of oxidative stress that will be measured include antioxidant enzymes of the ROS detoxification system, dietary intake of fruits and vegetables and more specifically by plasma carotenoids. Together, these measures provide a multi-pronged and integrated approach that addresses major aspects of mitochondrial dysfunction and oxidative stress that can be analyzed in humans. It will provide valuable information on the role of mitochondrial dysfunction and the mitochondrial related genetic variation in the risk of colorectal cancer, which will aid in the identification of high risk indivduals and may provide novel opportunities for prevention of colorectal cancer.

描述（由申请人提供）：线粒体功能障碍和活性氧（ROS）产生增加可能在包括结直肠癌在内的多种癌症的发病机制中发挥关键作用。大量研究表明线粒体是细胞中 ROS 的主要内源来源。 ROS 暴露增加会诱导线粒体和核 DNA 中的氧化 DNA 损伤以及细胞凋亡和炎症途径的激活。通过这些活动，ROS暴露可以导致细胞恶性转化。氧化损伤和恶变的程度受ROS解毒系统活性的影响。 ROS 产生和解毒的微妙变化受到环境因素和个体之间遗传变异的影响。虽然这些活动在细胞和动物研究中已得到充分证实，但很少有人研究评估线粒体功能障碍与结直肠癌风险之间的关系。我们将在一项频率匹配的巢式病例对照研究中前瞻性评估线粒体功能障碍、遗传变异、氧化损伤和 ROS 解毒系统等几个方面与结直肠癌之间的关联，该研究对一个完善的前瞻性队列中的 640 例结直肠癌病例和 1280 例对照进行研究，新加坡华人健康研究。线粒体功能障碍的指标包括线粒体 DNA 拷贝数、通过定量实时聚合酶链反应测量的线粒体 DNA 损伤以及通过尿液 F2-异前列腺素和血浆荧光氧化产物测量的氧化损伤。通过测量多态性和单倍群，评估线粒体基因组和与线粒体生物发生相关的核基因对氧化应激的遗传易感性。将测量的氧化应激的其他主要决定因素包括 ROS 解毒系统的抗氧化酶、水果和蔬菜的饮食摄入量，更具体地说是血浆类胡萝卜素的摄入量。这些措施共同提供了一种多管齐下的综合方法，解决可在人类中进行分析的线粒体功能障碍和氧化应激的主要方面。它将提供关于线粒体功能障碍和线粒体相关遗传变异在结直肠癌风险中的作用的有价值的信息，这将有助于识别高风险个体，并可能为预防结直肠癌提供新的机会。