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

基本信息

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
项目类别：
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

项目摘要

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。与年龄相关老年人血细胞突变是新发现的心血管疾病和血液学危险因素恶性肿瘤（HM）。这种风险背后的生物学机制尚不清楚。我们的研究仅限于老年妇女的原因我们已在研究计划中描述，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 (ERG)，导致功能丧失和表观遗传失调。表观遗传机制，例如 DNA 甲基化和组蛋白修饰，调节单核细胞如何发挥作用并对组织损伤做出反应。促炎单核细胞可加速血管中富含胆固醇的斑块形成并促进癌症的发展。永久突变改变单核细胞的表观遗传标记有利于炎症预计会产生有害的对人类疾病的影响。该项目的总体目标是定义生物学机制这是人类单核细胞中与年龄相关的 ERG 突变与增加之间关系的基础 CVD 和 HM 的风险。将从参加正在进行的一项研究的老年妇女身上采集新鲜血液样本题为“女性参与推进健康研究”（WEAR）的前瞻性队列研究于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），50 名无突变且与年龄和 CV 风险因素相匹配的老年女性（第 2 组），以及 20 名 18-45 岁之间、无突变的年轻女性（第 3 组）。第 3 组包含在本研究中以隔离老化的影响。我们有两个具体目标来实现该项目的目标：在目标 1 中，我们将进行全基因组 DNA 甲基化和 RNA 测序分析，并比较数据三个研究组定义了 ASXL1、DNMT3A 或 TET2 突变驱动的致病变化。这这项研究还将定义与衰老相关的影响。我们假设与年龄相关 ERG 突变诱导单核细胞致病性 DNA 甲基化和基因表达谱其特征在于与增强的存活、增殖和炎症相关。在目标 2 中，我们将确定突变型 ASXL1、DNMT3A 或 TET2 单核细胞（第 1 组）是否显示表型和使用既定方法与对照单核细胞（第 2 组和第 3 组）相比的功能异常评估单核细胞的活化和反应性。我们假设突变单核细胞表现出表型以及预测对损伤的过度促炎反应的功能标记物。这这些探索性研究的结果预计将产生新的假设并支持设计精确定义血细胞中这些与年龄相关的获得性基因突变如何发生的实验表现为涉及多个器官的疾病综合征，健康结果不佳。