Epigenetic Age as a Marker of Reproductive Age and Modifier of Invasive Breast Cancer Risk Among Postmenopausal Women

宾德博士的目标是成为一个领先的学术流行病学家在表观遗传规划的健康和 疾病，重点是癌症风险。她计划采用创新的方法 有效捕获基因调控中有生物学意义的变化的方法。宾德博士将与 广泛的科学家将这些机制研究的见解转化为改进， 卫生保健和疾病预防。到目前为止，她的研究主要集中在表观遗传模式的决定因素上 在子宫内和青春期建立。拟议的研究项目将把这方面的经验结合起来， 表观遗传修饰对绝经后乳腺癌发病率的影响。 表观遗传年龄是健康的预测因子，也是生物衰老的指标，它反映了以下因素的累积影响： 环境和行为对细胞功能的影响。先前的研究表明， 表观遗传衰老和癌症风险之间的相关性。巧合的是，生殖史表明 表观遗传年龄的降低与乳腺癌发病率的增加有关。因此我们假设 表观遗传年龄和生殖衰老过程之间存在临床相关的相互作用， 绝经后妇女的乳腺癌风险。我们建议分析表观年龄 在5，406名绝经后妇女中， 来自妇女健康倡议观察性研究和临床试验的妇女， 全基因组DNA甲基化。这将包括一个由1,382名妇女组成的子集， 雌二醇测量和285例浸润性乳腺癌。我们计划（1）描述 与生殖史相关的生育加速，（2）评估生活方式因素如何影响生育加速，（3） 分析β-Accel与生物可利用的雌二醇和睾酮之间的关系，（4）研究这些因素如何影响生物可利用的雌二醇和睾酮的水平。 激素可能会介导癌症风险的可改变和不可改变的预测因素并与之相互作用，从而产生影响 评估乳腺癌风险与乳腺癌风险之间的关系。这些目标一起 将把对生物衰老的影响与与癌症相关的实足年龄分开， 绝经后妇女的生育史。此外，这项工作将评估的实用性， 跟踪风险状况随时间的变化。为了进行这项研究，宾德博士将建立她的实质性的 通过有组织的指导，教学课程，附属机构， 与跨学科研究机构和相关研讨会。此外，宾德博士将产生新的 与癌症控制和预防专家建立研究伙伴关系，为她的分析方法提供信息， 解释。这项开发计划将建立宾德博士在表观遗传编程方面的声誉， 妇女的健康和癌症的风险，通过出版物和介绍，增加她的合作者网络， 并推动提交研究补助金，以促进她作为该领域独立调查员的职业生涯。

Dr. Binder's goal is to become a leading academic epidemiologist in the epigenetic programming of health and disease, with an emphasis on hormonally responsive cancer risk. She plans to apply innovative methodological approaches to efficiently capture biologically meaningful changes in gene regulation. Dr. Binder will collaborate with a broad spectrum of scientists to translate insight from these mechanistic studies into improvements in health care and disease prevention. Her research thus far has focused on determinants of epigenetic patterns established in utero and during puberty. The proposed research project will bridge this experience to study the impact of epigenetic modifications acquired across the life course on postmenopausal breast cancer incidence. Epigenetic age is a predictor of health and an indicator of biological aging, capturing the cumulative impact of environmental and behavioral influences across time on cellular function. Prior studies have suggested a positive correlation between epigenetic aging and cancer risk. Paradoxically, aspects of reproductive history suggested to decelerate epigenetic age are associated with increased breast cancer incidence. Therefore we hypothesize there is a clinically relevant interaction between epigenetic age and the process of reproductive aging on hormonally responsive cancer risk among postmenopausal women. We propose analyzing epigenetic age acceleration (AgeAccel; deviance between chronological and epigenetic age) within 5,406 postmenopausal women from the Women's Health Initiative Observational Study and Clinical Trial with previously measured genome-wide DNA methylation in whole blood. This will include a subset of 1,382 women with bioavailable estradiol measurements, and 285 cases of invasive breast cancer. We plan to (1) characterize the variation in AgeAccel associated with reproductive history, (2) assess how AgeAccel is influenced by lifestyle factors, (3) analyze the association between AgeAccel and bioavailable estradiol and testosterone, (4) investigate how these hormones may mediate and interact with modifiable and unmodifiable predictors of cancer risk to impact AgeAccel, and (5) estimate the association between AgeAccel and breast cancer hazard. Together these aims will separate the influences on biological aging from chronological age relevant for cancers associated with reproductive history among postmenopausal women. Additionally, this work will appraise the utility of AgeAccel to track the change in risk profile over time. To conduct this research, Dr. Binder will build her substantive knowledge of aging and postmenopausal health through organized mentorships, didactic coursework, affiliations with interdisciplinary research institutes and associated seminars. Furthermore, Dr. Binder will generate new research partnerships with experts in cancer control and prevention to inform her analytic approach and interpretations. This development plan will build Dr. Binder's reputation in the epigenetic programming of women's health and cancer risk through publications and presentations, increase her network of collaborators, and fuel the submission of a research grant to further her career as an independent investigator in this field.