Pathway Modeling of Complex Toxin Response and Energy Balance Systems in Cancer

描述（由申请人提供）：这个癌症预防，控制和人口科学职业发展奖被要求支持博士诺拉L。诺克成为一名独立的研究人员，专注于能量平衡和毒素反应系统的途径建模，以帮助确定运动和饮食干预措施，这将改善癌症的控制和预防。多环芳烃（PAHs）等毒素无处不在，可造成直接（PAH-DNA加合物）和间接氧化（8-氧代-dG）DNA损伤，以及其代谢、结合和DNA修复中的遗传多态性，与前列腺癌和结肠癌等多种癌症存在明确的相关性。身体活动（PA）是能量平衡的一个组成部分，一直与结肠癌相关，但其他癌症的报告不一致。此外，由于足够强度的运动可以上调抗氧化剂和其他毒素防御机制，并且亲脂性毒素（PAH）可以在身体脂肪中生物累积，因此身体活动和能量平衡的其他成分可能会改变毒素暴露的影响。为了进一步了解这些系统在致癌作用中的作用，需要基于生物系统的建模方法，将基因型，表型（基因表达）和其他流行病学数据。Nock博士接受过遗传流行病学培训，但需要在统计框架中进行额外的指导培训，以解决线性和非线性方程系统，包括结构方程建模（SEM）和基于生理学的毒理动力学/动态（PBTK/TD）建模，以进行此途径建模。诺克博士还将受益于营养和运动科学方面的明确培训。拟议的培训方案包括指导研究、研究生课程和在有关国家会议上的介绍。在研究计划中，Nock博士建议将基因型-表型和生物标志物措施整合到SEM和PBTK/TD统计框架中;并使用来自两项癌症研究的数据将这些方法应用于建模能量平衡和毒素反应系统。前列腺癌病例对照研究是独特的，因为它包括有效PAH剂量的生物标志物，PAH代谢中的候选基因，结合和DNA修复以及能量平衡测量。结肠息肉病例对照研究是能量学和癌症跨学科研究计划的一部分，可以评估能量平衡和毒素反应系统中的生物标志物和候选基因。

DESCRIPTION (provided by applicant): This Cancer Prevention, Control and Population Sciences Career Development Award is being requested to support the further development of Dr. Nora L. Nock into an independent investigator focusing on pathway modeling of energy balance and toxin response systems to help define exercise and diet interventions that will improve cancer control and prevention. Toxins such as polycyclic aromatic hydrocarbons (PAHs), which are ubiquitous and can create direct (PAH-DNA adduct) and indirect oxidative (8-oxo-dG) DNA damage, and genetic polymorphisms in their metabolism, conjugation and DNA repair have been equivocally associated with several cancers including prostate and colon. Physical activity (PA), a component of energy balance, has been consistently associated with colon cancer but reports in other cancers are inconsistent. Moreover, because exercise of sufficient intensity can upregulate antioxidant and other toxin defense mechanisms and lipophilic toxins (PAHs) can bioaccumulate in body fat, physical activity and other components of energy balance may modify effects of toxin exposure. To advance our knowledge of the role these systems play in carcinogenesis, biological systems-based modeling methods that incorporate genotype, phenotype (gene expression) and other epidemiological data are needed. Dr. Nock has been trained in genetic epidemiology but requires additional mentored training in statistical frameworks that solve systems of linear and non-linear equations including structural equation modeling (SEM) and physiologically-based toxico-kinetic/dynamic (PBTK/TD) modeling to undertake this pathway modeling. Dr. Nock would also benefit from explicit training in nutritional and exercise sciences. The proposed training program includes mentored research, graduate coursework and presentations at relevant national meetings. In the research plan, Dr. Nock proposes to integrate genotype-phenotype and biomarker measures into SEM and PBTK/TD statistical frameworks; and, apply these methods to modeling energy balance and toxin response systems using data from two cancer studies. The prostate cancer case-control study is unique because it includes biomarkers of effective PAH dose, candidate genes in PAH metabolism, conjugation and DNA repair and energy balance measures. The colon polyps case-control study is part of the Transdisciplinary Research on Energetics and Cancer program and enables evaluation of biomarkers and candidate genes in energy balance and toxin response systems.