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

表观遗传转录记忆在单核巨噬细胞和心血管疾病风险中的作用

• 批准号: 10444925
• 负责人: Michael Jay Corley
• 金额: $ 15.76万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10444925
• 关键词: Address; Affect; Age; Anti-Inflammatory Agents; Arterial Fatty Streak; Atherosclerosis; Bioinformatics; Biological Assay; Blood specimen; Cardiometabolic Disease; Cardiovascular Diseases; Caucasians; Cells; Centers of Research Excellence; Cholesterol; Clinical; Clinical Data; Clinical Immunology; Clinical Research; Core Facility; Cross-Sectional Studies; Cryopreservation; DNA; DNA Methylation; Data; Data Set; Development; Development Plans; Diabetes Mellitus; Endothelium; Ensure; Environment; Epigenetic Process; Ethnic Origin; Flow Cytometry; Foam Cells; Foundations; Functional disorder; Funding; Gender; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Hawaii; Health Disparities Research; Human; Immune; Immune system; Immunization; Immunology; In Vitro; Inflammation; Inflammatory; Innate Immune Response; Interdisciplinary Study; Knowledge; Measures; Memory; Mentored Research Scientist Development Award; Mentors; Mentorship; Metabolic; Metformin; Methods; Minority Groups; Molecular; Molecular Profiling; Morbidity - disease rate; Native Hawaiian; Native Hawaiian or Other Pacific Islander; Outcome; Pharmaceutical Preparations; Pilot Projects; Play; Polymerase Chain Reaction; Population; Protein Isoforms; RNA; Randomized Controlled Trials; Research; Research Infrastructure; Research Personnel; Research Project Grants; Research Training; Resource Sharing; Reverse Transcription; Role; Solid; Stimulus; Stress; Target Populations; Technology; Testing; Time; Training Programs; Translational Research; Universities; base; bead chip; bisulfite sequencing; cardiovascular disorder prevention; cardiovascular disorder risk; career; career development; cohort; effective intervention; epidemiology study; epigenetic regulation; epigenomics; ethnic disparity; experience; health disparity; high risk; macrophage; methylome; migration; modifiable risk; monocyte; mortality; multi-ethnic; multidisciplinary; precision medicine; programs; racial and ethnic; racial minority; responders and non-responders; response; skills; sociodemographics; success; transcriptome; transcriptome sequencing; uptake

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.

项目摘要/摘要 该建议详细介绍了一项为期五年的培训计划，以支持候选人实现他的 长期职业 建立成功的独立跨学科研究计划的目标，该计划具有临床，免疫学， 和表观遗传学研究，以解决表观遗传转录记忆在免疫细胞上的影响 少数民族人口中的心血管疾病（CVD）风险。 候选人具有强大的科学技能和 表观遗传学的知识提供了坚实的背景，以确保他在追求跨学科的成功 临床研究的重点是CVD。候选人试图集中于他的职业发展并增强他的职业发展 免疫学和临床CVD研究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，体外和前体单核细胞/巨噬细胞功能分析 人类细胞和综合生物信息学以建立他的独立性，以利用他的专业知识 表观遗传学解决CVD。他已经建立了自己的独立研究项目 定义跨种族的单核细胞/巨噬细胞细胞反应的表观遗传调节的作用 CVD健康分布。夏威夷大学的科学和机构环境匹配良好 确保候选人实现他的职业目标来研究免疫系统和CVD。有多个 独立资助的研究计划，例如心血管疾病研究中心，COBRE 糖尿病中心以及研究多学科和翻译研究基础设施扩展项目 这将提供共享的资源和核心设施，并在 心脏代谢疾病研究。研究职业发展计划的关键组成部分是Mentalship 来自一个专注于心血管疾病研究的多学科心理团队 免疫学，临床和健康差异研究专家致力于贡献其专业知识 支持候选人的职业发展并扩大他的研究培训。候选人将追求 假设功能失调的单核细胞反应与 高心血管疾病风险与炎症和 与高加索人相比，夏威夷原住民的代谢基因会加剧。为了检验这一假设， 来自200名本地夏威夷人和年龄性别的过度冷冻保存血样的横断面研究 研究项目旨在解决 匹配具有临床定义高和低CVD风险的高加索人。具体目的是（1）衡量和 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 多民族队列中临床定义的低或高CVD风险。 （2）确定是否表观遗传调节 来自NHOPI和高加索人与CVD的分离的单核细胞中的炎症和代谢基因 风险和种族不同。 （3）在高CVD风险NHOPI和高加索人的单核细胞中，检查 二甲双胍对炎症和代谢基因的表观遗传状态的影响。

项目成果

A machine learning approach utilizing DNA methylation as an accurate classifier of COVID-19 disease severity.

• DOI: 10.1038/s41598-022-22201-4
• 发表时间: 2022-10-19
• 期刊: Scientific reports
• 影响因子: 4.6

Longitudinal Study of DNA Methylation and Epigenetic Clocks Prior to and Following Test-Confirmed COVID-19 and mRNA Vaccination.

• DOI: 10.3389/fgene.2022.819749
• 发表时间: 2022
• 期刊: Frontiers in genetics
• 影响因子: 3.7

The impacts of social determinants of health and cardiometabolic factors on cognitive and functional aging in Colombian underserved populations.

• DOI: 10.1007/s11357-023-00755-z
• 发表时间: 2023-08
• 期刊: GEROSCIENCE
• 影响因子: 5.6
• 作者: Santamaria-Garcia, Hernando;Moguilner, Sebastian;Rodriguez-Villagra, Odir Antonio;Botero-Rodriguez, Felipe;Pina-Escudero, Stefanie Danielle;O'Donovan, Gary;Albala, Cecilia;Matallana, Diana;Schulte, Michael;Slachevsky, Andrea;Yokoyama, Jennifer S.;Possin, Katherine;Ndhlovu, Lishomwa C.;Al-Rousan, Tala;Corley, Michael J.;Kosik, Kenneth S.;Muniz-Terrera, Graciela;Miranda, J. Jaime;Ibanez, Agustin
• 通讯作者: Ibanez, Agustin

Shifts in the immunoepigenomic landscape of monocytes in response to a diabetes-specific social support intervention: a pilot study among Native Hawaiian adults with diabetes.

• DOI: 10.1186/s13148-022-01307-6
• 发表时间: 2022-07-18
• 期刊: Clinical epigenetics
• 影响因子: 5.7

Neurocognitive impact of Zika virus infection in adult rhesus macaques.

• DOI: 10.1186/s12974-022-02402-4
• 发表时间: 2022-02-07
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Hsu DC;Chumpolkulwong K;Corley MJ;Hunsawong T;Inthawong D;Schuetz A;Imerbsin R;Silsorn D;Nadee P;Sopanaporn J;Phuang-Ngern Y;Klungthong C;Reed M;Fernandez S;Ndhlovu LC;Paul R;Lugo-Roman L;Michael NL;Modjarrad K;Vasan S
• 通讯作者: Vasan S