Investigating the Role of a Lifestyle Intervention on Novel Estrogen Biomarkers

描述（由申请人提供）： 背景：大量证据表明雌激素与乳腺癌和子宫内膜癌的发展有关。儿茶酚雌激素 (CE) 途径中的雌激素代谢物，特别是羟基雌激素 (HE) 醌，能够形成 DNA 加合物，在某些情况下可能导致 DNA 突变。因此，HE 醌参与致癌作用的生物学合理性，加上 CE 代谢是可逆的这一事实，表明该途径是干预研究中理想的靶向途径。除了这项研究与国家护理研究所对整合生物学和行为的重点以及阐明涉及 CE 途径的可改变因素的潜力非常一致之外，该项目还允许候选人获得培训，以发展成为一名独立的研究人员。方法：Reding 博士拥有从流行病学角度研究儿茶酚雌激素途径的背景，建议接受行为和护理研究方面的培训，以便在临床环境中采用认知行为治疗 (CBT) 方法实施干预。生活方式干预将侧重于激励来自初级保健诊所的患有乳腺癌和/或子宫内膜癌高风险的患者，并引导久坐的生活方式开始改变，以改善饮食并增加体力活动。除了指导阶段的正式培训外，申请人还将在现有的 CBT 干预研究中获得研究经验，并利用来自现有研究人群的 125 名女性进行试点研究，以表征新型生物标志物，即羟基雌激素结合加合物 (HEBA) 及其未结合的对应物（具体目标 1）。在独立阶段，候选人将进行可行性研究，以确定在目标人群中实施生活方式干预的可行性（具体目标 2），确定该人群中生物标志物的变异性（具体目标 3），并探索干预措施对身体成分的影响（具体目标 4）。结果：试点和可行性研究的结果将用于为 R01 申请提供初步数据，该申请建议调查饮食和运动干预可以影响 CE 途径中代谢物平衡的假设，特别关注新型生物标志物。结论：K99 奖励机制将促进 Reding 博士的职业发展，使候选人能够在新的研究方向（即基于行为的临床干预的实施）发展专业知识，以实现她获得教职的长期职业目标，在那里她将能够开展独立的研究，调查生活方式干预对生物机制的影响。 公共健康相关性：该职业发展提案的主要目标是让候选人做好准备进行旨在改善女性饮食和运动习惯的干预措施，该提案与国家护理研究所对健康促进的关注非常一致，特别是因为它涉及旨在长期维持健康行为的干预措施的开发。当前研究的生物行为重点可能有助于阐明健康的饮食和运动行为如何降低荷尔蒙相关癌症的风险。此外，成功的生活方式干预还可能对降低多种慢性疾病的风险产生影响，包括心血管疾病和糖尿病。

DESCRIPTION (provided by applicant): Background: There is a large accumulation of evidence implicating estrogen in breast and endometrial cancer development. Estrogen metabolites within the catechol estrogen (CE) pathway, in particular hydroxy estrogen (HE) quinones, are capable of forming DNA adducts which may lead in certain instances to DNA mutations. Thus, the biological plausibility of the involvement of the HE quinones in the initiation of carcinogenesis coupled with the fact that CE metabolism is reversible indicates that this pathway is ideal for targeting in an intervention study. In addition to this research being well aligned with the National Institute of Nursing Research's focus on integrating biology and behavior, and its potential for elucidating modifiable factors involved the CE pathway, this project also allows for the candidate to gain training in order to develop into an independent researcher. Methods: Having a background studying the catechol estrogen pathway from an epidemiologic perspective, Dr. Reding proposes to gain training in behavioral and nursing research in order to implement an intervention employing a cognitive behavioral therapy (CBT) approach based in a clinical setting. The lifestyle intervention will focus on motivating patients from primary care clinics who are at a high risk for breast and/or endometrial cancer and leading a sedentary lifestyle to initiate changes to improve their diet and increase their physical activity. In addition to formal training during the mentored phase, the applicant will gain research experiences within existing studies of CBT interventions, as well as conduct a pilot study using 125 women from a well-characterized, existing study population in order to characterize the novel biomarkers, namely hydroxy estrogen bound-adducts (HEBA) and their unbound counterparts (Specific Aim 1). During the independent phase, the candidate will implement a feasibility study in order to identify the practicability of implementing a lifestyle intervention within the target population (Specific Aims 2), determine the variability of the biomarker in this population (Specific Aim 3) and explore the impact of the intervention on body composition (Specific Aim 4). Results: The results from the pilot and feasibility studies will be used to provide preliminary data for an R01 application proposing to investigate the hypothesis that a diet and exercise intervention can impact the balance of metabolites in the CE pathway with a particular focus on novel biomarkers. Conclusion: The K99 award mechanism will foster Dr. Reding's career growth by enabling the candidate to develop expertise in a new direction of research, namely in the implementation of behaviorally based clinical interventions, in order to reach her long-term career goals of attaining a faculty position where she would be able to launch an independent line of research investigating the impact of lifestyle interventions on biological mechanisms. PUBLIC HEALTH RELEVANCE: With the main goal of this career development proposal being to prepare the candidate to conduct interventions aimed at improving women's dietary and exercise habits, this proposal is well aligned with the National Institute of Nursing's focus on health promotion, particularly as it relates to the development of interventions designed to sustain healthy behaviors over time. The biobehavioral focus within the current study could help to shed light on how healthy dietary and exercise behaviors reduce the risk of hormonally-related cancers. In addition, a successful lifestyle intervention could also have implications in reducing the risk of multiple chronic diseases, including cardiovascular disease and diabetes.