Epigenomics of Neurocognitive Function in Breast Cancer

乳腺癌神经认知功能的表观基因组学

• 批准号: 10414032
• 负责人: CATHERINE M. BENDER
• 金额: $ 40.17万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414032
• 关键词: Address; Age; Anxiety; Architecture; Aromatase Inhibitors; Attention; Biological; Brain; Breast Cancer Treatment; Cognitive; DNA; DNA Methylation; Data; Data Collection; Development; Disease; Enrollment; Exercise; Fatigue; Gene Expression Regulation; Genes; Health; Impaired cognition; Individual; Interdisciplinary Study; Intervention; Investigation; Knowledge; Malignant Neoplasms; Measures; Mediating; Mental Depression; Mitochondria; Neurocognition; Neurocognitive; Newly Diagnosed; Nuclear; Pathway interactions; Phenotype; Postmenopause; Prevention strategy; Randomized; Research; Sampling; Short-Term Memory; Sleep Disorders; Sleep disturbances; Symptoms; Therapeutic Intervention; Time; Woman; associated symptom; brain health; cognitive function; cost effectiveness; effective therapy; epigenomics; evidence base; executive function; exercise intervention; gray matter; improved; inhibitor therapy; malignant breast neoplasm; methylation pattern; methylome; neuroimaging; novel; phenotypic data; recruit; sample collection; treatment as usual; treatment strategy; white matter; whole genome

Neurocognitive changes with breast cancer and its treatment are significant symptoms in the majority of women with this disease. Unfortunately, very little is known about the mechanisms that underlie these neurocognitive changes, which in turn limits the development of effective treatments and prevention strategies. Evidence supports that DNA methylation impacts cognitive function (CF) and brain health (BH), exercise impacts DNA methylation, and exercise impacts CF and BH. Although investigating DNA methylation patterns has potential to uncover novel biological underpinnings to help us understand neurocognitive changes within the context of breast cancer and its treatment, no DNA methylation study has evaluated the interrelationships among CF, BH and exercise within the context of breast cancer and its treatment. The purpose of the proposed study is to examine the dynamic DNA methylome to identify genes and biological pathways that are involved with CF and BH within the context of breast cancer and its treatment. This project capitalizes on data and samples generated through an ongoing project that involves women newly diagnosed with early stage breast cancer who will receive aromatase inhibitor (AI) therapy and randomizes them to an exercise intervention or usual care. Because breast cancer and AI therapy impact CF and BH in a negative manner and exercise impacts CF and BH in a positive manner; this project offers an exemplar, unique opportunity to identify biological mechanisms involved in CF and BH within the context of breast cancer and its treatment. Phenotype data for CF will focus on cognitive domains that deteriorate with AI therapy including attention, working memory, and executive function, and brain health will be measured using neuroimaging including regional gray matter volume, white matter architecture, and functional dynamics of the brain. Cognitive function may be mediated by commonly occurring symptoms therefore this study will include evaluating fatigue, sleep problems, depression, and anxiety for their potential to mediate or moderate the impact of DNA methylation on CF and BH. Whole genome DNA methylation data will be generated for all women at two time points: at enrollment when all women will be pre AI therapy and not yet randomized and post 6 months intervention for those randomized to the exercise intervention and usual care. This allows us to address mechanisms for CF and BH within the context of breast cancer prior to therapy, within the context of AI therapy, and within the context of an exercise intervention. An additional aim of this project will replicate significant findings using data and DNA samples from a project that recruits older healthy individuals, randomizes them to an identical exercise intervention, similarly measures CF and BH phenotypes, and collects biological samples at the same time points. Findings from this project have the potential to inform evidence based, mechanistically driven therapeutic interventions to mitigate the negative consequences of cancer and its treatment.

乳腺癌及其治疗引起的神经认知变化是大多数患者的显着症状 患有这种疾病的女性。不幸的是，人们对这些现象背后的机制知之甚少。 神经认知的变化，反过来又限制了有效治疗和预防策略的发展。 有证据表明 DNA 甲基化会影响认知功能 (CF) 和大脑健康 (BH)、运动 影响 DNA 甲基化，运动影响 CF 和 BH。尽管研究 DNA 甲基化模式 有潜力发现新的生物学基础，帮助我们理解神经认知的变化 在乳腺癌及其治疗的背景下，尚无 DNA 甲基化研究评估其相互关系 在乳腺癌及其治疗的背景下，CF、BH 和运动之间的关系。目的 拟议的研究是检查动态 DNA 甲基化组，以确定基因和生物途径 涉及乳腺癌及其治疗背景下的 CF 和 BH。该项目充分利用数据 以及通过一个正在进行的项目生成的样本，该项目涉及新诊断为早期阶段的女性 患有乳腺癌的患者将接受芳香酶抑制剂 (AI) 治疗并随机分配进行锻炼 干预或常规护理。因为乳腺癌和 AI 治疗会对 CF 和 BH 产生负面影响，并且 锻炼对 CF 和 BH 产生积极影响；该项目提供了一个典型的、独特的机会 确定乳腺癌及其治疗背景下 CF 和 BH 涉及的生物学机制。 CF 的表型数据将重点关注因人工智能治疗而恶化的认知领域，包括注意力、 将使用神经影像学来测量工作记忆、执行功能和大脑健康，包括 区域灰质体积、白质结构和大脑的功能动态。认知功能 可能是由常见症状介导的，因此这项研究将包括评估疲劳、睡眠 问题、抑郁和焦虑，因为它们有可能介导或减轻 DNA 甲基化的影响 CF 和 BH。将为所有女性在两个时间点生成全基因组 DNA 甲基化数据： 当所有女性将接受 AI 治疗前且尚未随机分组且在 6 个月干预后进行登记时 那些随机接受运动干预和常规护理的人。这使我们能够解决 CF 的机制 和 BH 在治疗前的乳腺癌背景下、在 AI 治疗背景下以及在 运动干预的背景。该项目的另一个目标是使用数据复制重要发现 以及来自一个项目的 DNA 样本，该项目招募老年健康个体，将他们随机分配到相同的组中 运动干预，类似地测量CF和BH表型，并同时收集生物样本 时间点。该项目的研究结果有可能为基于证据的、机械驱动的提供信息 减轻癌症及其治疗的负面影响的治疗干预措施。

项目成果

Methylation Data Processing Protocol and Comparison of Blood and Cerebral Spinal Fluid Following Aneurysmal Subarachnoid Hemorrhage.

动脉瘤性蛛网膜下腔出血后的甲基化数据处理方案以及血液和脑脊液的比较。

• 发表时间: 2020
• 作者: Arockiaraj, Annie I;Liu, Dongjing;Shaffer, John R;Koleck, Theresa A;Crago, Elizabeth A;Weeks, Daniel E;Conley, Yvette P
• 通讯作者: Conley, Yvette P