Genetic Epidemiology of Insulin Resistance Pathway Factors and Colon Cancer

描述(申请人提供)：建议的K22奖项将支持李詈，医学博士，博士从一名导师转变为一名独立的癌症遗传流行病学研究员。在达蒙·鲁尼恩癌症研究基金会支持的指导研究期间，他发展了专注于基因-环境相互作用的癌症遗传学/分子流行病学方面的专业知识，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，预计到他的导师临床研究员奖结束时，总共将有1100个病例和对照可用于这一应用。 K22的提案将使用一种新的结构方程模型方法，通过将胰岛素抵抗综合征与结肠癌作为一个整体的关系来解决胰岛素抵抗-结肠癌假说。这项研究有望获得对胰岛素抵抗-结肠联系的新的和关键的洞察力，通过将综合征的每个代谢成分视为独立协变量，使用传统的“独立风险因素发现”回归分析可能遗漏或扭曲了这些联系。此外，这项K22提案将在三个分子途径和两个环境因素(即体力活动和非类固醇抗炎药物(NSAIDs))中综合评估9个候选基因的SNPs和单倍型，这些因素与胰岛素抵抗和结肠癌的发生有关。具体地说，这项建议有以下目的：1)评估胰岛素抵抗综合征与结肠癌的关系；2)从三个分子途径研究结肠癌与9个候选基因的SNPs和单倍型的关系：(I)胰岛素-生长激素-IGF-胰岛素受体底物轴，(Ii)炎症，和(Iii)脂肪生成；3)研究这些遗传和环境因素在结肠癌中的直接和间接作用(即，由胰岛素抵抗介导)。 这项研究将填补目前在理解长期能量失衡导致的胰岛素抵抗与结肠癌之间潜在联系方面的知识空白。它将为计划中的R01全面申请奠定基础，以寻求国家资金，将目前的努力扩大到一项全面研究，以解决胰岛素抵抗-结肠癌假说的统一主题下的基因-环境联合作用。

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.