Defining monocyte abnormalities caused by age-associated mutations in epigenetic regulatory genes

定义由表观遗传调控基因年龄相关突变引起的单核细胞异常

• 批准号: 9295868
• 负责人: Kim-Hien T Dao
• 金额: $ 19.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295868
• 关键词: Abnormal Monocyte; Acute Myelocytic Leukemia; Address; Adhesives; Adopted; Age; Aging; Animal Model; Area; Arterial Fatty Streak; Atherosclerosis; Bioinformatics; Biological; Biology; Blood Cells; Blood Platelets; Blood specimen; Cardiovascular Diseases; Cause of Death; Cells; Cessation of life; Characteristics; Cholesterol; Clinical; Complex; DNA Methylation; DNA Sequence Alteration; Data; Development; Diet; Disease; Dysmyelopoietic Syndromes; Early Diagnosis; Enrollment; Epigenetic Process; Gene Expression; Gene Expression Profile; Gene Frequency; Gene Mutation; Genetic; Genetic study; Genomics; Goals; Guidelines; Health; Health Sciences; Heart; Hematologic Neoplasms; Hematopoiesis; Hematopoietic Neoplasms; Human; Hypermethylation; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Left; Link; Loss of Heterozygosity; Malignant Neoplasms; Measures; Methodology; Methylation; Molecular Profiling; Monitor; Mono-S; Mus; Mutation; Oregon; Organ; Outcome; Pathogenicity; Patients; Phenotype; Prospective cohort; Prospective cohort study; Regulator Genes; Research; Risk; Risk Factors; Role; Rupture; Syndrome; Technology; Testing; Tissues; Universities; Woman; Work; age effect; bead chip; cardiovascular disorder risk; cardiovascular risk factor; chemokine; cohort; cytokine; design; experimental study; genetic variant; genome wide methylation; genome-wide; hazard; histone modification; human disease; human old age (65+); improved; insight; loss of function; loss of function mutation; macrophage; monocyte; mutant; next generation; older women; oxidized lipid; predictive marker; research study; response to injury; targeted treatment; tool; transcriptome sequencing; treatment strategy; young woman

Project abstract Cardiovascular disease (CVD) remains the leading cause of death among older people. Age-associated mutations in blood cells of older people are newly discovered risk factors for CVD and hematologic malignancy (HM). The biological mechanisms underlying this risk are not yet known. Our study is limited to older women for the reasons we have described in the research plan but the research findings will have widespread application in older people. The most common acquired mutations occur in ASXL1, DNMT3A, and TET2, collectively referred as epigenetic regulatory genes (ERGs), result in loss-of-function and epigenetic dysregulation. Epigenetic mechanisms, e.g., DNA methylation and histone modification, regulate how monocytes function and respond to tissue injury. Pro-inflammatory monocytes can accelerate cholesterol-rich plaque formation in vessels and promote cancer development. Mutations that permanently change the epigenetic marks of monocytes in favor of inflammation are expected to produce detrimental consequences in human diseases. The overall goal of the project is to define the biological mechanisms that underlie the relationship between age-associated ERGs mutations in human monocytes and increased risk for CVD and HM. Fresh blood samples will be collected from older women enrolled in an ongoing prospective cohort study entitled Women Engaged in Advancing health Research (WEAR) conducted at Oregon Health & Science University. We will evaluate 50 older women with ASXL1, DNMT3A, or TET2 mutations (group 1), 50 older women without mutations matched for age and CV risk factors (group 2), and 20 younger women between 18-45 years old without mutations (group 3). Group 3 is included in this study to isolate the effect of aging. We have two specific aims to address the goals of the project: In aim 1, we will conduct genome-wide DNA methylation and RNA sequencing analyses and compare the data among the three study groups to define the pathogenic changes driven by ASXL1, DNMT3A, or TET2 mutations. The effects associated with aging will also be defined in this study. We hypothesize that age-associated mutations in ERGs induce a pathogenic DNA methylation and gene expression profile in monocytes characteristically associated with enhanced survival, proliferation, and inflammation. In aim 2, we will determine whether mutant ASXL1, DNMT3A, or TET2 monocytes (group 1) display phenotypic and functional abnormalities compared to control monocytes (groups 2 and 3) using established methodologies that evaluate monocyte activation and reactivity. We hypothesize that mutant monocytes display phenotypic and functional markers that are predictive of an exaggerated pro-inflammatory response to injury. The findings from these exploratory studies are expected to generate new hypotheses and support the design of experiments that precisely define how these age-associated, acquired genetic mutations in blood cells are manifesting as a disease syndrome involving multiple organs with poor health outcomes.

项目摘要 心血管疾病(CVD)仍然是老年人死亡的主要原因。与年龄相关的 老年人血细胞突变是新发现的心血管疾病和血液病的危险因素 恶性肿瘤(HM)。这种风险背后的生物学机制尚不清楚。我们的研究仅限于 我们在研究计划中描述的原因是年龄较大的女性，但研究结果将 在老年人中广泛应用。最常见的获得性突变发生在ASXL1、DNMT3A、 和TET2，统称为表观遗传调节基因(ERGs)，导致功能丧失和 表观遗传失调。表观遗传机制，如DNA甲基化和组蛋白修饰，调节 单核细胞的功能和对组织损伤的反应。促炎症单核细胞可以加速 富含胆固醇的斑块在血管中形成，并促进癌症的发展。永久性的突变 改变单核细胞表观遗传标志有利于炎症有望产生有害影响 对人类疾病的后果。该项目的总体目标是定义生物机制 这是人类单核细胞中与年龄相关的ERGs突变和增加之间的关系的基础 心血管疾病和高血压的风险。新鲜血液样本将从参加正在进行的 一项名为《女性从事先进健康研究(WEAR)》的前瞻性队列研究在 俄勒冈健康与科学大学。我们将评估50名患有ASXL1、DNMT3A或TET2的老年女性 突变(第1组)，没有年龄和心血管危险因素匹配的50名老年女性(第2组)，以及 20名年龄在18-45岁之间且无突变的年轻女性(第3组)。第三组包括在本研究中 以隔离衰老的影响。我们有两个具体目标来解决该项目的目标：在目标1中，我们将 进行全基因组DNA甲基化和RNA测序分析，并比较 三个研究小组定义由ASXL1、DNMT3A或TET2突变驱动的致病变化。这个 与衰老相关的影响也将在这项研究中定义。我们假设与年龄相关的 ERGs基因突变诱导单核细胞致病DNA甲基化和基因表达谱 具有增强的存活率、增殖和炎症的特点。在目标2中，我们将 确定突变的ASXL1、DNMT3A或TET2单核细胞(第1组)是否表现出表型和 使用已建立的方法与对照单核细胞(组2和组3)进行比较的功能异常 来评估单核细胞的激活和反应性。我们假设突变的单核细胞表现出表型 以及功能标记物，它们可以预测对损伤的夸大的促炎反应。这个 这些探索性研究的结果有望产生新的假设，并支持 精确定义这些与年龄相关的血细胞获得性基因突变的实验 表现为涉及多个器官的疾病综合征，健康结局不佳。