Genetic Epidemiology of Insulin Resistance Pathway Factors and Colon Cancer

描述（由申请人提供）：拟议的K22奖将支持李立，医学博士，博士从一个受指导的人变成了一个独立的癌症遗传流行病学研究者。在Damon Runyon癌症研究基金会支持的指导研究期间，他发展了他在癌症遗传/分子流行病学方面的专业知识，重点是基因-环境相互作用，并建立了基于肯塔基州SEER登记的结肠癌事件病例对照研究。这项研究已经从580多个病例和人群对照中收集了血液样本和数据，预计在他指导的临床研究者奖结束时，将累计提供1,100个病例和对照。 K22提案将通过使用新的结构方程模型方法来研究胰岛素抵抗综合征与结肠癌的整体关系，从而解决胰岛素抵抗-结肠癌假说。这项研究有望获得新的和关键的洞察胰岛素抵抗-结肠的联系，可能已经错过或扭曲的研究使用传统的“独立的风险因素发现”回归分析，通过治疗综合征的每个代谢成分作为独立的协变量。此外，本次K22提案将综合评估三条分子途径和两个环境因素中9个候选基因的SNP和单倍型，即，体力活动和非甾体抗炎药（NSAIDS），涉及胰岛素抵抗和结肠癌的发展。具体而言，本提案具有以下目的：1）评估胰岛素抵抗综合征作为一个整体与结肠癌的关系; 2）检查结肠癌与三个分子途径中的9个候选基因的SNP和单倍型的关系：（i）胰岛素-生长因子-IGF-胰岛素受体底物轴，（ii）炎症，和（iii）脂肪生成; 3）调查直接和间接（即，由胰岛素抵抗介导）这些遗传和环境因素对结肠癌的影响。 这项研究将填补目前的知识空白，了解长期能量失衡导致的胰岛素抵抗与结肠癌之间的潜在联系。它将为计划中的完整R 01申请奠定基础，以寻求国家资金，将目前的努力扩展到一项完全有效的研究，以解决胰岛素抵抗-结肠癌假设统一主题下的基因-环境联合行动。

DESCRIPTION (provided by applicant): The proposed K22 award will support the transition of Li Li, M.D., Ph.D. from a mentored to an independent cancer genetic epidemiology investigator. During his mentored research supported by Damon Runyon Cancer Research Foundation, he has developed his expertise in cancer genetic/molecular epidemiology focusing on gene-environment interaction, and established a Kentucky SEER Registry-based incident case-control study of colon cancer. This study has already collected blood samples and data from over 580 cases and population controls, and it is anticipated that a total of 1,100 cases and controls will be accrued and available for this application by the end of his mentored Clinical Investigator Award. The K22 proposal will address the insulin resistance-colon cancer hypothesis by looking at the relation of insulin resistance syndrome as an integral entity with colon cancer using a novel structure equation model approach. This study holds promise of gaining novel and critical insight into the insulin resistance-colon link that might have been missed or distorted in studies using the conventional 'independent risk factor finding' regression analysis by treating each of the metabolic components of the syndrome as independent covariates. In addition, this K22 proposal will comprehensively evaluate SNPs and haplotypes of 9 candidate genes in three molecular pathways and two environmental factors, i.e., physical activity and non-steroidal anti-inflammatory drugs (NSAIDS), implicated in the development of insulin resistance and colon carcinogenesis. Specifically, this proposal has the following aims: 1) To assess the relation of insulin resistance syndrome as an integral entity with colon cancer; 2) To examine the relations of colon cancer with SNPs and haplotypes of 9 candidate genes in three molecular pathways: (i) insulin-growth hormone-IGF-insulin receptor substrate axis, (ii) inflammation, and (iii) adipogenesis; 3) To investigate the direct and indirect (i.e., mediated by insulin resistance) effects of these genetic and environmental factors on colon cancer. This research will fill current knowledge gaps in understanding the underlying link between insulin resistance resulting from long-term energy imbalance and colon cancer. It will set the stage for a planned full R01 application to seek national funding to expand the current effort to a fully powered study to tackle gene-environment joint action under the unifying theme of insulin resistance-colon cancer hypothesis.