Aspirin and Cancer Prevention in Lynch Syndrome: From Cell to Population Data

阿司匹林与林奇综合征的癌症预防：从细胞数据到群体数​​据

• 批准号: 8759524
• 负责人: Ajay Goel
• 金额: $ 59.6万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-23 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759524
• 关键词: Affect; Age; Aspirin; Burn injury; Cell Death; Cell Line; Cell division; Cells; Colon Carcinoma; Colorectal Cancer; Complex; DNA; Data; Death Rate; Dose; Dura Mater; Environment; Epidemiology; Evolution; Genes; Germ-Line Mutation; Goals; Growth; Hereditary Nonpolyposis Colorectal Neoplasms; Human; In Vitro; Incidence; Individual; Inflammation; Inherited; Investigation; Kinetics; Laboratories; Laws; Link; Mediating; Microsatellite Instability; Mismatch Repair; Modeling; Mus; Mutation; Patients; Pattern; Penetrance; Population; Probability; Relative (related person); Testing; cancer prevention; carcinogenesis; cell growth; early onset; in vivo; insight; mathematical model; protective effect; public health relevance; repaired; research study; tool; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): Lynch syndrome patients inherit a germline mutation in one of several DNA mismatch repair (MMR) genes, leading to a significantly earlier onset and a higher penetrance of colorectal cancer than in sporadic cases due to the occurrence of microsatellite instability (MSI). Long term administration of aspirin has been shown to reduce the incidence of colon cancer in Lynch syndrome patients, as documented by epidemiological data. The mechanisms underlying this effect are not fully understood. It is thought that protection is achieved through COX-dependent and independent activities. Basic kinetic parameters, such as the division rate, death rate, and mutation rate of cells have been shown to be affected. In order to better understand how protection is achieved, it is important to find out how changes in cellular parameters determine the degree of protection observed on the population level. The hypothesis is explored that the degree of protection observed on the population level can be predicted from data that quantify how aspirin changes parameters related to the evolutionary dynamics of cells. This hypothesis will be tested with an inter-disciplinary approach that combines experiments with mathematical models and that links data on cellular kinetics with those on incidence in the population. The firs two aims will quantify the extent to which aspirin changes a set of key parameters that are related to the growth and evolution of cells. These include the rate of cell division, the rate of ell death, the rate at which genetic changes are incurred, the probability of repair, the mean duration of repair, etc. This will be done with different cell lines exposed to varying levels of inflammation. The investigation starts first in an in vitro setting and is then extended to human tumor xenografts in mice, which represent a more complex growth environment for the cells. Subsequently, the data on cellular kinetics will inform a mathematical model of in vivo carcinogenesis in Lynch Syndrome patients. The model will be used to generate theoretical age-incidence curves for colon cancer in Lynch syndrome patients in the presence and absence of aspirin treatment. It will test whether the model can successfully predict the observed age-incidence curves through model application to epidemiological data. The model will allow us to determine which cellular parameter(s) contribute the most to the protection observed in the population data, and to explore possible avenues to enhance this level of protection. Implications of our results for understanding aspirin-mediated protection against sporadic colorectal cancer will be explored by analyzing appropriate epidemiological data.

描述（由申请人提供）：林奇综合征患者遗传了几种 DNA 错配修复 (MMR) 基因之一的种系突变，由于微卫星不稳定性的发生，导致结直肠癌比散发病例明显更早发病，外显率更高（微星）。流行病学数据证明，长期服用阿司匹林可以降低林奇综合征患者结肠癌的发病率。这背后的机制 效果尚未完全了解。据认为，保护是通过 COX 依赖和独立的活动来实现的。细胞的分裂率、死亡率和突变率等基本动力学参数已被证明受到影响。为了更好地了解如何实现保护，重要的是要找出细胞参数的变化如何决定在群体水平上观察到的保护程度。研究假设，在群体水平上观察到的保护程度可以通过量化阿司匹林如何改变与细胞进化动力学相关的参数的数据来预测。这一假设将通过跨学科方法进行检验，该方法将实验与数学模型相结合，并将细胞动力学数据与人群发病率数据联系起来。前两个目标将量化阿司匹林改变一组与细胞生长和进化相关的关键参数的程度。这些包括细胞分裂的速率、细胞死亡率、发生遗传变化的速率、修复的概率、修复的平均持续时间等。这将通过暴露于不同程度的炎症的不同细胞系来完成。该研究首先在体外环境中开始，然后扩展到小鼠的人类肿瘤异种移植物，这代表了细胞更复杂的生长环境。随后，细胞动力学数据将为林奇综合征患者体内致癌的数学模型提供信息。该模型将用于生成林奇综合征患者在接受和不接受阿司匹林治疗的情况下结肠癌的理论年龄发病率曲线。它将通过模型应用到流行病学数据来测试该模型是否能够成功预测观察到的年龄发病率曲线。该模型将使我们能够确定哪些细胞参数对群体数据中观察到的保护贡献最大，并探索提高这种保护水平的可能途径。我们将通过分析适当的流行病学数据来探讨我们的结果对于了解阿司匹林介导的散发性结直肠癌保护作用的意义。