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

基本信息

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
项目类别：
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

项目摘要

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）：Lynch综合征患者在几种DNA不匹配修复（MMR）基因之一中继承了一种种系突变，导致大肠癌的发作明显早，并且由于发生了微卫星不稳定性（MSI）而引起的结直肠癌的渗透率更高。如流行病学数据所记录的那样，已证明阿司匹林的长期给药可降低林奇综合征患者的结肠癌的发生率。这是基础的机制效果尚未完全理解。人们认为，通过依赖Cox的独立活动来实现保护。基本动力学参数，例如分裂率，死亡率和细胞突变率已被证明受到影响。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确定人口水平上观察到的保护程度。探索了该假设，即可以从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中预测在人群水平上观察到的保护程度。该假设将通过跨学科的方法进行检验，该方法将实验与数学模型结合在一起，并将细胞动力学的数据与人群发病率联系起来。 FIRS两个目标将量化阿司匹林改变与细胞生长和演变有关的一组关键参数的程度。其中包括细胞分裂的速率，ELL死亡率，遗传变化发生的速率，修复的可能性，平均修复持续时间等。这将以暴露于不同水平的炎症水平的不同细胞系来完成。研究首先在体外环境中开始，然后将其扩展到小鼠的人类肿瘤异种移植物，这代表了细胞的更复杂的生长环境。随后，有关细胞动力学的数据将为林奇综合征患者体内癌变的数学模型提供信息。该模型将用于在存在和不存在阿司匹林治疗的情况下，在林奇综合征患者中为结肠癌生成理论年龄的曲线。它将测试模型是否可以通过模型应用于流行病学数据成功预测观察到的年龄段曲线。该模型将使我们能够确定哪种蜂窝参数对人群数据中观察到的保护贡献最大，并探索可能提高这种保护水平的途径。通过分析适当的流行病学数据，将探讨我们对了解阿司匹林介导的对零星结直肠癌的保护的影响。