The impact of biobehavioral factors and aspirin on ovarian cancer biology

生物行为因素和阿司匹林对卵巢癌生物学的影响

• 批准号: 10761655
• 负责人: GUILLERMO N ARMAIZ-PENA
• 金额: $ 14.46万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761655
• 关键词: ADRB2 gene; Adrenergic Receptor; Anxiety; Aspirin; Attenuated; Biological; Biological Assay; Black race; Cancer Biology; Cancer Center; Carcinoma; Case Series; Case/Control Studies; Chronic stress; Clinical; Data; Development; Diagnosis; Disease; Distress; Dose; Emotional; Enzyme-Linked Immunosorbent Assay; Epithelial ovarian cancer; Ethnic Origin; Evaluation; Future; Gene Expression; Genes; Goals; Health Sciences; Hispanic; Hormones; Hospitals; Human; Immune; Immune response; Immunity; Immunosuppression; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intervention; Latina; Lead; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Mental Depression; Mus; Norepinephrine; Not Hispanic or Latino; Outcome; Pathway interactions; Patient Self-Report; Patients; Pharmacotherapy; Population Heterogeneity; Population Intervention; Population Study; Prevention strategy; Process; Prospective cohort; Prostaglandins; Puerto Rico; Race; Reporting; Research; Research Project Grants; Resources; Risk; Role; Sampling; Science; Serous; Services; Stress; Sympathetic Nervous System; Time; Tissues; Tumor Immunity; Tumor Tissue; Tumor-associated macrophages; Universities; Up-Regulation; Woman; Work; adaptive immunity; biobank; biobehavior; bisphosphonate; cancer risk; cancer survival; carcinogenicity; education research; epidemiologic data; ethnic disparity; ethnic diversity; exome; experience; high risk; immune function; improved; innovation; mouse model; novel; outreach; ovarian cancer prevention; ovarian neoplasm; pharmacologic; population based; prevent; prospective; psychosocial; racial disparity; racial diversity; response; restraint stress; systemic inflammatory response; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis

ABSTRACT | FULL RESEARCH PROJECT 2 Growing evidence indicates that the biological response to chronic stress and subsequent distress can promote the progression of epithelial ovarian cancer via prolonged activation of the sympathetic nervous system and sustained norepinephrine release. Downstream consequences of norepinephrine exposure include increased prostaglandin-related inflammation and an immunosuppressive landscape. Conversely, increasing evidence supports the role of aspirin use in ovarian cancer prevention and survival. Yet, key questions remain about the underlying biological mechanism of action of chronic stress/distress and aspirin use (considering low and standard doses separately) and their interrelationship with ovarian cancer biology. Specifically, we propose to evaluate the hypothesis that distress enhances ovarian cancer progression by promoting inflammatory and immune processes and that aspirin abrogates these effects. Our innovative study uses unique population-based and experimental resources. Aim 1 will use data from four long-term prospective cohorts in diverse populations, a population-based case-control study, a hospital case series that collected self-reported measures of chronic stress and distress (e.g., depression), and ovarian tumor tissue. Aim 1 will measure gene expression in bulk high grade serous tumor samples (to capture the full tumor microenvironment) using whole exome RNASeq. We hypothesize that distress is associated with the up- regulation of inflammation-related and immune suppression gene expression pathways that is normalized among aspirin users. We will also assess if the association of distress with ovarian cancer risk is attenuated among aspirin users. Notably, we are leveraging racially and ethnically diverse studies that have highly characterized ovarian cancer cases, allowing assessment of differences in association by race (Black, White) and ethnicity (Hispanic, non-Hispanic), as well as the examination of associations between distress- related gene expression profiles and clinical outcomes. Using an orthogonal and interactive approach, Aim 2 will use experimental ovarian cancer mouse models to characterize the progressive effect over time of daily restraint stress on tumor inflammation and immunity as well as ovarian tumor growth, using RNASeq and stress hormones measured via ELISA assays. We also will examine if aspirin (recapitulating equivalents of low and standard dose aspirin in humans) counteracts the effects of chronic stress on tumor progression and inflammatory and immune gene expression networks. This project will leverage the scientific services of several cores, including the Puerto Rico BioBank (PRBB) and the Quantitative Science Core (QSC), with substantial interaction with the Outreach Core, the Planning and Evaluation Core, and working with trainees in the Research Education Core. This innovative application will inform future work to develop novel immuno- preventive strategies, pharmacotherapies, and psychosocial interventions to prevent and treat invasive ovarian cancer in women who experience chronic stress and distress.

摘要|完整的研究项目2 越来越多的证据表明，对慢性压力和随后困扰的生物学反应可以 通过长期激活交感神经来促进上皮卵巢癌的进展 系统和持续的去甲肾上腺素释放。去甲肾上腺素暴露的下游后果 包括增加前列腺素相关的炎症和免疫抑制景观。反过来， 越来越多的证据支持阿司匹林在卵巢癌预防和生存中的作用。但是，关键 关于慢性应激/痛苦和阿司匹林作用的基本生物学机制仍然存在问题 使用（分别考虑低剂量和标准剂量）及其与卵巢癌生物学的相互关系。 具体而言，我们建议评估以下假设，即遇险通过 促进炎症和免疫过程，阿司匹林消除了这些作用。我们的创新研究 使用独特的基于人群的和实验资源。 AIM 1将使用四个长期的数据 一项基于人群的病例对照研究的不同人群中的潜在人群，这是一个医院病例系列 收集的自我报告的慢性应激和困扰（例如抑郁症）和卵巢肿瘤组织的措施。 AIM 1将测量大量高级浆液肿瘤样品中的基因表达（捕获完整的肿瘤 微环境）使用整个Exome Rnaseq。我们假设困扰与上升有关 调节炎症相关和免疫抑制基因表达途径，该途径已归一 在阿司匹林用户中。我们还将评估遇险与卵巢癌风险的关联是否受到衰减 在阿司匹林用户中。值得注意的是，我们利用具有高度的种族和种族多样性研究 特征是卵巢癌病例，允许评估种族的关联差异（黑色， 白色）和种族（西班牙裔，非西班牙裔），以及对遇险之间的关联的检查 相关的基因表达谱和临床结果。使用正交和互动方法，目标2 将使用实验性卵巢癌小鼠模型来表征每日时间的渐进效应 使用RNASEQ和 通过ELISA测定法测得的应力激素。我们还将检查阿司匹林是否（概括 人类中的低和标准剂量阿司匹林应对慢性应激对肿瘤进展的影响 炎症和免疫基因表达网络。该项目将利用 几个核心，包括波多黎各生物库（PRBB）和定量科学核心（QSC）， 与外展核心，计划和评估核心以及与受训者合作的实质性互动 研究教育核心。这种创新的应用将为未来的工作提供信息，以开发新颖的免疫接种 预防策略，药物治疗和社会心理干预措施，以预防和治疗侵入性 经历慢性压力和困扰的女性的卵巢癌。