Investigating Socio-Structural Determinants of Health and the Tumor Epigenome to Understand the Etiology of Racial Disparities in Breast Cancer

项目摘要/摘要 该项目的首要目标是研究健康的社会结构决定因素如何影响乳房。 肿瘤DNA甲基组，致癌信号的激活，最终，种族差异的发展 三阴性乳腺癌(TNBC)TNBC中种族差异的病因学基础尚不清楚 很少有研究调查健康的社会决定因素作为差异的潜在驱动因素的影响。 McCullough小组最近的研究表明，在亚特兰大，患有乳腺癌的黑人女性更多 比起白人女性(80%比20%)，更有可能生活在红线社区，而且生活在高失业率的地区 红线标记与乳腺癌死亡率增加60%有关。这些数据支持以下需求 调查红线是导致TNBC种族差异的原因。我们假设，为了实现健康公平，它 有必要了解社会结构性不平等如何在生物学上不利地表现出来，从而导致 在乳腺癌方面。这项研究的目的是阐明一种解释这种联系的生物学机制。 社区层面的红线和TNBC中的差异之间的关系。这项调查需要一名具有 多样化的技能，可以解决从人口到替补席的问题。这条通往独立的道路 Miller-Kleinhenz博士的获奖申请(K99/R00)旨在独特地定位她来回答这些问题 通过建立她以前在乳腺肿瘤生物学方面的专业知识，并扩大她在社会和分子领域的技能 流行病学和表观遗传学。为了实现这项研究的目标，Miller-Kleinhenz博士将专注于她的培训 在三个方面，(1)通过全面的教学课程增加知识，(2)体验和 从不同的研究环境中学习，以及(3)通过领导力促进专业发展， 科学交流，然后过渡到独立。这些培训目标将由一个 由劳伦·麦卡洛博士领导的跨学科辅导团队，研究了癌症健康差异和分子 流行病学专家，埃默里大学罗林斯公共卫生学院流行病学助理教授 大学。共同导师将是癌症生物学家、血液学教授亚当·马库斯博士 和肿瘤学以及Winship癌症研究所的临时执行主任。这项培训将帮助Dr。 Miller-Kleinhenz将在K99阶段实现以下目标：理解红线作为一种 与TNBC发展(目标1)和检查有关的健康的社会结构决定因素 TNBC中乳腺肿瘤表观基因组的红线相关DNA甲基化特征(目标2)。在.期间 R00期，她将确定红线相关致癌基因表达的病理生物学意义 TNBC中的信号通路(目标3)。这项为期5年的研究和培训计划将使Miller-Kleinhenz博士能够 建立独立的研究计划，阐明政策干预的新途径，并 将有助于减少癌症健康差距这一最终目标的药物治疗。

Project Summary/ Abstract The overarching goal of this project is to examine how socio-structural determinants of health impact the breast tumor DNA methylome, activation of oncogenic signaling and ultimately, the racially disparate development of triple negative breast cancer (TNBC). The etiologic basis of racial disparities in TNBC is not well understood and few studies have investigated the impact of social determinants of health as potential drivers of disparities. Recent work from the McCullough group shows that, in Atlanta, Black women with breast cancer are more likely to live in redlined neighborhoods than White women (80% vs 20%) and that living in areas with high rates of redlining is associated with a 60% increase in breast cancer mortality. These data support the need to investigate redlining as an etiologic driver of race disparities in TNBC. We posit that to achieve health equity, it is necessary to understand how socio-structural inequities can be adversely manifested biologically, resulting in breast cancer. The goal of this study is to elucidate a biological mechanism that explains the association between neighborhood-level redlining and disparities in TNBC. This investigation requires a researcher with a diverse skillset that can address questions from the population to the bench. This Pathway to Independence Award (K99/R00) application by Dr. Miller-Kleinhenz intends to uniquely position her to answer these questions by building on her prior expertise in breast tumor biology and expanding her skill set in social and molecular epidemiology and epigenetics. To achieve the aims of this research, Dr. Miller-Kleinhenz will focus her training in three areas, (1) increasing knowledge through a comprehensive didactic curriculum, (2) experiencing and learning from varied research environments, and (3) fostering professional development through leadership, scientific communication, and then transitioning to independence. These training goals will be supervised by an interdisciplinary mentoring team, led by Dr. Lauren McCullough, a cancer health disparities and molecular epidemiology expert and an Assistant Professor of Epidemiology at Rollins School of Public Health at Emory University. The co-mentor will be Dr. Adam Marcus, an expert cancer biologist and a Professor of Hematology and Oncology and the Interim Executive Director of the Winship Cancer Institute. This training will aid Dr. Miller-Kleinhenz to pursue the following aims during the K99 phase: Understanding the impact of redlining as a social-structural determinant of health that is associated with TNBC development (Aim 1) and examining redlining-associated DNA methylation signatures of the breast tumor epigenome in TNBC (Aim 2). During the R00 phase, she will determine the pathobiological significance of redlining-associated expression of oncogenic signaling pathways in TNBC (Aim 3). This 5-year research and training plan will allow Dr. Miller-Kleinhenz to establish an independent research program that will elucidate new avenues for policy interventions and pharmacological treatments that would contribute to the ultimate goal of reducing cancer health disparities.