The Interplay of Behavior, Environment, and Microbiota in Colorectal Cancer Risk

 描述（由申请人提供）：蒂芙尼卡森博士是一名应用流行病学家，有研究黑人和白色妇女健康差异的背景。卡森博士的早期工作重点是与饮食、体育活动、肥胖和相关健康结果相关的行为。最近，卡森博士专注于应用她的研究成果，以更好地了解黑人和白色妇女的癌症差异。卡森博士的首要职业目标是成为一名独立资助的研究人员，并开发基于证据的生物行为干预措施，以减少癌症健康差异。为此，本申请提出了一个严格的研究项目和培训计划，重点是调查微生物群作为黑人和白色女性之间结直肠癌（CRC）差异的新的潜在贡献者。CRC是美国癌症死亡的第二大原因 占癌症死亡人数的9%。CRC的已知风险因素包括年龄增长、男性、家族史、炎症性肠病、2型糖尿病、饮酒、吸烟、缺乏身体活动、大量食用红肉和加工肉类以及高脂肪饮食和肥胖。在妇女中，即使考虑到风险因素分布的差异，黑人妇女患CRC的风险仍比白色妇女高48%。越来越多的研究表明，饮食对CRC风险的影响是通过微生物群介导的，饮食，生活方式和抗生素引起的微生物扰动可能导致CRC和其他慢性疾病的风险增加。压力是已被证明会导致微生物群改变的一个因素。我们的研究表明，黑人妇女报告中度到高度的压力水平和其他出版的文献表明，黑人妇女报告更高的压力水平比他们的白色同行。这些观察结果导致我们的假设，即与白色女性相比，由于更高的压力水平，黑人女性的微生物群受到干扰的比例更大，这使得黑人女性患CRC的风险更大。在本提案中，我们计划采用病例对照研究设计来探索这一假设，比较以下两组：1）来自UAB Kirklin诊所的黑人和白色女性CRC事件，2）年龄匹配的无癌症黑人和白色女性社区对照。具体来说，我们将首先描述患有CRC的黑人和白色女性的口腔和肠道微生物群，并通过种族进行比较，特别关注已知与CRC正相关或负相关的微生物。因为所有病例都有CRC，我们假设在微生物群或其他已知的CRC风险因素（如饮食）中没有显著的种族差异。相比之下，当我们在无癌症的黑人和白色女性社区对照中重复这项实验时，我们希望观察到微生物群的种族差异，黑人女性比白色女性具有更少的健康促进细菌和更多的致病细菌，这将使黑人女性患CRC的风险增加。我们预计，对照组中更大比例的黑人女性将拥有与CRC参与者相似的微生物群。此外，如果我们的假设得到支持，心理压力与健康促进细菌呈负相关，与致病细菌呈正相关。我们的研究结果将深入了解迄今为止尚未充分探索的生活方式因素，如压力可能与CRC风险相关，因为压力如何干扰微生物群。如果我们确定压力通过微生物扰动导致CRC风险，则可以开发和实施未来的生物行为干预措施，包括压力管理和饮食/补充建议以促进粘膜健康，从而降低CRC风险，这可能导致与诊断和治疗相关的医疗保健成本降低，并减少黑人和白色女性之间的CRC差异。除了提供有价值的数据外，拟议的研究项目还将为卡森博士作为一名独立资助的生物行为癌症差异研究人员的发展提供额外培训的机会。卡森博士将参加密集的结构化培训，通过完成以下内容来发展专业知识：1）在招募不同种族的临床和社区人口进行生物标本和生物库研究方面的培训，2）获得生物信息学技术的实践和教学培训，以及3）提高专业技能，如团队科学，网络，赠款写作，指导，高影响力的出版物。在受人尊敬的导师和合作者小组的指导下，以及在伯明翰的亚拉巴马大学提供的高质量的研究和培训环境下，卡森博士的研究和培训经验将为科学界和卡森博士的整体职业发展做出重大贡献。

 DESCRIPTION (provided by applicant): Dr. Tiffany Carson is an applied epidemiologist with a background in studying health disparities of black and white women. Dr. Carson's early work focused on behaviors related to diet, physical activity, obesity and related health outcomes. Recently, Dr. Carson has focused on applying her research efforts to better understand cancer disparities of black and white women. Dr. Carson's overarching career goal is to become an independently funded investigator and develop evidence-based bio-behavioral interventions to reduce cancer health disparities. To that end, this application proposes a rigorous research project and training plan focused on investigating the microbiota as a novel potential contributor to colorectal cancer (CRC) disparities between black and white women. CRC is the 2nd leading cause of cancer death in the United States accounting for 9% of cancer deaths. Known risk factors for CRC include increasing age, male sex, family history, inflammatory bowel disease, type 2 diabetes, alcohol consumption, smoking, physical inactivity, high consumption of red and processed meats and high fat diet, and obesity. Among women, even after accounting for differences in the distribution of risk factors, black women remain at 48% greater risk for CRC than white women. There is a growing body of research suggesting that the influence of diet on CRC risk is mediated through the microbiota and that microbial perturbations caused by diet, lifestyle, and antibiotics can lead to increased risk for CRC and other chronic diseases. Stress is one factor that has been shown to lead to alterations in the microbiota. Our research has shown that black women report moderate to high stress levels and additional published literature indicates that black women report higher stress levels than their white counterparts. These observations have lead to our hypothesis that a greater proportion of black women have a perturbed microbiota as a result of higher stress levels compared to white women, putting black women at greater risk for developing CRC. In the present proposal, we plan to explore this hypothesis employing a case control study design comparing the following groups: 1) black and white women with incident CRC from the Kirklin Clinic at UAB and 2) age-matched cancer-free black and white female community controls. Specifically, we will first characterize the oral and gut microbiota of black and white women with CRC and compare by race with particular focus on microbes known to be either positively or negatively associated with CRC. Because all cases will have CRC, we hypothesize that there will be no significant racial differences in the microbiota or other known risk factors for CRC such as diet. In contrast, when we repeat this experiment in cancer-free black and white female community controls, we expect to observe racial differences in the microbiota, with black women having less health-promoting bacteria and more pathogenic bacteria than white women, which would put black women at increased risk for CRC. We anticipate that a greater proportion of black females in the control group will have microbiota that resembles the microbiota of participants with CRC. Additionally, if our hypothesis is supported, psychological stress with be inversely associated with health-promoting bacteria and positively associated with pathogenic bacteria. Our findings will provide insight into how lifestyle factors that have not been fully explored to date such as stress may be associated with risk for CRC as a result of how stress perturbs the microbiota. If we determine that stress contributes to CRC risk via microbial perturbations, future bio-behavioral interventions that incorporate stress management and dietary/supplemental recommendations to promote mucosal health, and therefore reduce CRC risk, can be developed and implemented which could lead to diminished health care costs related to diagnosis and treatment and reduce CRC disparities between black and white women. In addition to providing valuable data, the proposed research project will also provide the opportunity for the additional training needed for Dr. Carson's development as an independently funded bio-behavioral cancer disparities researcher. Dr. Carson will engage in an intensive, structured training experience to develop expertise by completing the following: 1) Training in the recruitment of racially diverse clinical and community populations for bio-specimen and bio-banking research, 2) Obtaining hands-on and didactic training in bioinformatics techniques, and 3) Improving professional skills such as team science, networking, grant writing, mentoring, and high-impact publications. Under the guidance of an esteemed panel of mentors and collaborators and the high quality research and training environment that the University of Alabama at Birmingham offers, Dr. Carson's research and training experiences will make a significant contribution to the scientific community and Dr. Carson's overall career development.