The role of epigenetic transcriptional memory in monocyte-macrophage cells and cardiovascular disease risk

项目总结/摘要 该提案详细说明了一个为期五年的培训计划，以支持候选人实现其 长期职业 目标是建立一个成功的独立的跨学科研究计划，以临床，免疫学， 和表观遗传学研究，以解决免疫细胞中表观遗传转录记忆的影响， 心血管疾病（CVD）的风险在少数群体。 候选人有很强的科学技能， 表观遗传学知识，提供了坚实的背景，以确保他在追求跨学科的成功 临床研究主要集中在CVD。候选人寻求专注于他的职业发展，并提高他的 在免疫学和临床CVD研究方面的经验和技术研究技能。候选人将获得 基本的研究技能，包括流式细胞术，体外和离体单核细胞/巨噬细胞功能测定 人类细胞，和综合生物信息学，以建立他的独立性，利用他的专业知识， 表观遗传学来治疗心血管疾病他已经建立了自己的独立研究项目， 定义了不同种族单核细胞/巨噬细胞反应的表观遗传调节作用， CVD健康差异。夏威夷大学的科学和制度环境非常匹配 以确保候选人实现他的职业目标，研究免疫系统和CVD。有多个 独立资助的研究项目，如心血管疾病研究中心，COBRE 糖尿病中心和研究多学科和转化研究基础设施扩建项目 这将提供共享资源和核心设施，并提供许多合作机会， 心脏代谢疾病研究。研究职业发展计划的一个关键组成部分是导师制 来自一个专注于心血管疾病研究的多学科指导团队， 免疫学，临床和健康差异研究专家致力于贡献他们的专业知识， 支持候选人的职业发展并扩大其研究培训。候选人将追求一个 假设单核细胞反应功能障碍与 高心血管疾病风险与炎性和非炎性表观基因组编程差异有关， 与高加索人相比，夏威夷土著人的代谢基因和恶化。为了验证这一假设， 对200名夏威夷原住民和年龄性别的可行冷冻保存血液标本的横断面研究 研究项目旨在解决 匹配临床定义的高和低CVD风险的高加索人。具体目标是：（1）测量和 比较来自NHOPI和高加索人的分离的单核细胞和巨噬细胞的功能反应， 多种族队列中临床定义的低或高CVD风险。(2)确定表观遗传调节是否 NHOPI和高加索人分离单核细胞中炎症和代谢基因与CVD相关 风险和种族不同。(3)在来自高CVD风险NHOPI和高加索人的单核细胞中， 二甲双胍对炎症和代谢基因表观遗传状态的影响。

Project Summary/Abstract This proposal details a five-year training program to support the candidate to achieve his long-term career goal of building a successful independent transdisciplinary research program featuring clinical, immunology, and epigenetic research to address the impact of epigenetic transcriptional memory in immune cells on cardiovascular disease (CVD) risk in minority populations. The candidate has a strong scientific skillset and knowledge in epigenetics that provides a solid background to ensure his success in pursuing transdisciplinary clinical research focused on CVD. The candidate seeks to focus his career development and enhance his experience and technical research skills in immunology and clinical CVD research. The candidate will acquire essential research skills including flow cytometry, in vitro and ex-vivo monocyte/macrophage functional assays of human cells, and integrative bioinformatics to establish his independence in using his expertise in epigenetics to address CVD. He has already established his own independent research project aimed at defining the role of epigenetic regulation of monocyte/macrophage cellular responses across ethnicities with CVD health disparities. The scientific and institutional environment at the University of Hawaii is well-matched to ensuring the candidate achieves his career goals to study the immune system and CVD. There are multiple independently funded research programs such as the Center for Cardiovascular Disease Research, COBRE Diabetes Center, and Research Multidisciplinary and Translational Research Infrastructure Expansion project that will provide shared resources and core facilities and offer numerous collaborative opportunities in cardiometabolic disease research. A key component of the research career development plan is mentorship from a multi-disciplinary mentoring team focused on cardiovascular disease research consisting of immunology, clinical, and health disparity research experts committed toward contributing their expertise to support the candidate’s career development and expand his research training. The candidate will pursue a hypothesis that dysfunctional monocyte responses associated with high cardiovascular disease risk are related to epigenomic programming differences at inflammatory and metabolic genes and are exacerbated in Native Hawaiians compared to Caucasians. To test this hypothesis, a cross-sectional study of viably cryopreserved blood specimens from 200 Native Hawaiians and age gender research project aimed at addressing the matched Caucasians with clinically defined high and low CVD risk. The specific aims are (1) To measure and compare functional responses of isolated monocyte and macrophage cells from NHOPI and Caucasians with clinically defined low or high CVD risk in the Multiethnic cohort. (2) Determine if epigenetically regulated inflammatory and metabolic genes in isolated monocyte cells from NHOPI and Caucasians associate with CVD risk and differ by ethnicity. (3) Within monocytes from high CVD risk NHOPI and Caucasians, to examine the impact of metformin on the epigenetic state of inflammatory and metabolic genes.