Immune Activation and Immunosenescence Biomarkers and Cardiovascular Disease Risk

免疫激活和免疫衰老生物标志物与心血管疾病风险

• 批准号: 9229576
• 负责人: Nels C. Olson
• 金额: $ 11.15万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9229576
• 关键词: Academic Training; Adaptive Immune System; Address; Adult; Advisory Committees; American; American Heart Association; Ancillary Study; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Area; Atherosclerosis; Autoantibodies; Award; B-Lymphocytes; Basic Science; Behavioral; Biochemical Genetics; Biochemistry; Biological Assay; Biological Markers; Biometry; Biostatistical Methods; Budgets; C-reactive protein; CD14 gene; CD28 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiovascular Diseases; Cardiovascular Manifestation; Cardiovascular system; Cell Culture System; Cells; Cellular biology; Cessation of life; Chronic; Clinical; Clinical Research; Clinical Trials; Coagulation Process; Code; Cohort Studies; Common carotid artery; Contracts; Cross-Sectional Studies; Data; Death Rate; Development; Discipline; Disease; Doctor of Philosophy; Epidemiology; Epithelial; Epithelial Cells; Etiology; Event; FCGR3B gene; Factor XII; Faculty; Fellowship; Funding; Future; Gene Silencing; Genetic; Goals; Health; Helper-Inducer T-Lymphocyte; Human; Hypoxia Inducible Factor; Immune; Immunity; Immunobiology; Immunoglobulins; Immunologic Markers; Individual; Individual Differences; Inflammation; Inflammatory; International; Intervention; Joints; Knockout Mice; Knowledge; LDL Cholesterol Lipoproteins; Laboratories; Laboratory Technicians; Low-Density Lipoproteins; Lymphocyte; Manuscripts; Measures; Medical; Medicine; Memory; Mentors; Mentorship; Metabolism; Molecular; Molecular Biology; Molecular Epidemiology; Morbidity - disease rate; Multi-Ethnic Study of Atherosclerosis; Myocardial Infarction; National Heart, Lung, and Blood Institute; National Institute of Environmental Health Sciences; Nitric Oxide; Nitric Oxide Synthase; Participant; Pathology; Peer Review; Pharmacology; Phase; Phenotype; Physiological; Plasma; Population; Positioning Attribute; Postdoctoral Fellow; Predictive Factor; Preparation; Prevention; Public Health; Publishing; Regulation; Regulatory T-Lymphocyte; Research; Research Design; Research Institute; Research Personnel; Research Project Grants; Resources; Risk; Risk Factors; Risk stratification; Role; Severities; Signal Transduction; Smoking; Supervision; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Th2 Cells; Thick; Thrombin; Training; Translating; Universities; Vermont; Work; allergic airway disease; assay development; atherogenesis; attributable mortality; base; cardiovascular disorder risk; cardiovascular health; cardiovascular risk factor; career; clinical practice; college; coronary artery calcification; cost; disorder risk; epidemiology study; follow-up; genetic epidemiology; human population study; hypoxia inducible factor 1; immune activation; immunosenescence; improved; inflammatory marker; inter-individual variation; meetings; member; memory CD4 T lymphocyte; monocyte; mortality; multidisciplinary; novel; novel therapeutic intervention; oxidized low density lipoprotein; population based; post-doctoral training; pre-doctoral; professor; programs; prospective; public health relevance; research study; response; scavenger receptor; senescence; treatment strategy

 DESCRIPTION (provided by applicant): Dr. Nels C. Olson, PhD is a postdoctoral fellow in the Laboratory for Clinical Biochemistry Research (LCBR) in the Department of Pathology and Laboratory Medicine at the University of Vermont College of Medicine. He is currently supported by an NHLBI-funded T32 training award and is mentored by Dr. Russell P. Tracy, PhD, director of the LCBR, Professor of Pathology and Biochemistry, and the Department's Vice-Chair for Research. Dr. Olson earned a PhD in cell and molecular biology at the University of Vermont under the mentorship of Dr. Albert van der Vliet, PhD as an NIEHS-funded T32 predoctoral trainee. Dr. Olson's research thesis utilized isolated primary airway epithelial cell culture systems, hypoxia-inducible factor-1α (HIF-1α) gene silencing, and nitric oxide synthase 2 genetic knock out mice, to elucidate the roles of nitric oxide and HIF-1 signaling in airway epithelial barrier regulation during allergic airway disease. Dr. Olson's career goals are to become an independent faculty member with a research program that involves the joint application of epidemiological, biochemical, genetic, and biostatistical methods to develop inflammation-, immunity-, and coagulation-based biomarker assays for implementation and use in cardiovascular disease (CVD) epidemiological and clinical research studies. His goals are to elucidate disease etiology, translate molecular findings to human populations, improve CVD risk stratification, and guide individual treatment strategies. In order to achieve these goals, Dr. Olson chose to pursue postdoctoral training in molecular epidemiology with Dr. Tracy following the completion of his basic science oriented PhD. Dr. Olson's current research involves investigating biomarkers of inflammation (TNF-α, C-reactive protein), immunity (Th1 and Th2 cells, CD4+ memory and naive cells), and coagulation (thrombin, coagulation factors XII, XI and IX) as CVD risk factors in large population-based epidemiological cohort studies (e.g., the Multi-Ethnic Study of Atherosclerosis (MESA); the Cardiovascular Health Study (CHS)). During his postdoctoral fellowship, Dr. Olson, has published 8 manuscripts and was awarded the American Heart Association's (AHA) Roger R. Williams award for genetic epidemiology and the prevention and treatment of atherosclerosis. Dr. Olson serves on the ancillary studies committee for the NHLBI-MESA study, and attends and presents at the MESA steering committee meetings, and the AHA Epidemiology Scientific Sessions. He also serves on the Early Career Advisory Committee of the Cardiovascular Research Institute of Vermont. Dr. Olson's research application proposes to measure 17 T- and B-lymphocyte and monocyte populations, and novel plasma-based biomarkers of immunocyte activation, at the baseline examinations of MESA and CHS. Using a case-cohort study design with 2,400 participants free of CVD at baseline, Dr. Olson will evaluate the prospective relationships of these immune cell subpopulations with the future onset of myocardial infarction (MI) and the composite endpoint of incident MI and new onset angina. The research hypothesis contains three main features: 1) high levels of pro-inflammatory cells (Th1, Th17, B2, CD8+, and classical monocytes (CD14+CD16-)) with direct roles in atherosclerosis will increase the risk of CVD events; 2) a high degree of chronic adaptive immune activation will increase the risk of CVD events; and, 3) high levels of anti-inflammatory cells (Th2, Treg, B1, non-classical monocytes, T follicular helper cells) will decrease the risk of CVD events. The proposed research reflects Dr. Olson's career goals in the joint application of multiple disciplines: epidemiological cohort studies, immunobiology assay development, and biostatistical analyses. During the K99 phase of the award, Dr. Olson will gain expertise in research assay development and laboratory management (e.g., budget preparation, technician supervision, etc.) by supervising a laboratory budget (beyond that awarded by the K99) and a laboratory technician while developing assays proposed in the research. Dr. Tracy will provide these resources, oversee the research progress, and provide mentoring. Dr. Olson will obtain academic training in biostatistics and epidemiology, required for his goals of becoming an independent investigator in epidemiological research, by completing an on-line Master's in Public Health degree offered by the University of Vermont over the first 2 years of the K99/R00 award. He will also receive individual mentoring on specific aspects of the research project from a multi-disciplinary Advisory Committee. During the R00 phase of the award Dr. Olson will execute an independent research program developing biomarkers related to B cell biology, B cell immunoglobulin subclasses, and immune cell co- stimulation and metabolism, and evaluating their relationships with incident CVD; areas which are not being pursued by Dr. Tracy. To continue to build an independent research program, Dr. Olson will develop and prepare an R01 in the first year of the R00 phase and submit the application during the second R00 year. Dr. Tracy is the Director of the Core Laboratory for CHS and MESA and has over 500 peer-reviewed manuscripts in CVD-epidemiology, inflammation, immunity, biomarker assays, and several other research areas. Dr. Tracy currently has 16 actively funded contracts and awards and is centrally involved in several national and international epidemiology studies, clinical studies, and clinical trials. Dr. Tracy is committed to mentoring and training Dr. Olson to transition into a successful independent faculty position.

 描述（由申请人提供）：Nels C. Olson 博士是佛蒙特大学医学院病理学和实验医学系临床生物化学研究实验室 (LCBR) 的博士后研究员，目前获得资助。获得 NHLBI 资助的 T32 培训奖，并由 LCBR 主任、病理学和生物化学教授、该系副主席 Russell P. Tracy 博士指导。研究。Olson 博士在佛蒙特大学获得细胞和分子生物学博士学位，并获得 NIEHS 资助的 T32 博士前实习生 Albert van der Vliet 博士的指导。Olson 博士的研究论文利用了分离的原代气道上皮细胞。培养系统、缺氧诱导因子-1α (HIF-1α) 基因沉默和一氧化氮合酶 2 基因敲除小鼠，以阐明Olson 博士的职业目标是成为一名独立的教员，从事一项涉及流行病学、生化、遗传和生物统计学方法联合应用开发的研究项目。基于炎症、免疫和凝血的生物标志物测定，用于心血管疾病 (CVD) 流行病学和临床研究中的实施和使用，他的目标是阐明疾病病因、转化分子水平。为了实现这些目标，奥尔森博士在完成基础科学博士学位后，选择跟随特雷西博士进行分子流行病学博士后培训。 Olson 目前的研究涉及炎症（TNF-α、C 反应蛋白）、免疫（Th1 和 Th2 细胞、CD4+ 记忆细胞和幼稚细胞）和凝血（凝血酶、凝血因子）的生物标志物Olson 博士在博士后研究期间，将 XII、XI 和 IX）作为大规模人群流行病学队列研究中的 CVD 危险因素（例如，动脉粥样硬化多种族研究 (MESA)；心血管健康研究 (CHS)）。发表了8篇手稿，并因遗传流行病学和动脉粥样硬化的预防和治疗而荣获美国心脏协会（AHA）罗杰·R·威廉姆斯奖。他是 NHLBI-MESA 研究的辅助研究委员会成员，并出席 MESA 指导委员会会议和 AHA 流行病学科学会议。 Olson 的研究应用建议在 MESA 和 CHS 的基线检查中测量 17 种 T 淋巴细胞和 B 淋巴细胞和单核细胞群体，以及新型血浆免疫细胞激活生物标志物。 Olson 博士采用病例队列研究设计，有 2,400 名基线时没有 CVD 的参与者，将评估这些免疫细胞亚群与未来心肌梗死 (MI) 发病以及 MI 事件和新发心绞痛的复合终点之间的前瞻性关系。研究假设包含三个主要特征：1）高水平的促炎细胞（Th1、Th17、B2、CD8+和经典单核细胞） （CD14+CD16-））在动脉粥样硬化中具有直接作用，会增加 CVD 事件的风险；2）高度的慢性适应性免疫激活会增加 CVD 事件的风险；3）高水平的抗炎细胞（ Th2、Treg、B1、非经典单核细胞、滤泡辅助性T细胞）将降低CVD事件的风险。拟议的研究反映了Olson博士在多学科联合应用中的职业目标：流行病学队列研究、免疫生物学测定开发和生物统计分析 在奖励的 K99 阶段，Olson 博士将通过监督实验室预算获得研究测定开发和实验室管理（例如预算准备、技术人员监督等）方面的专业知识。 （超出 K99 授予的）和实验室技术员在开发研究中提出的检测方法时将提供这些资源，监督研究进展，并提供指导。奥尔森博士将获得以下方面的学术培训。通过在 K99/R00 奖项的前两年完成佛蒙特大学提供的在线公共卫生硕士学位，他将获得生物统计学和流行病学知识，这是他成为流行病学研究独立调查员的目标所必需的。多学科咨询委员会对研究项目的具体方面进行个人指导 在奖项的 R00 阶段，Olson 博士将执行一项独立研究计划，开发与 B 细胞生物学、B 细胞免疫球蛋白相关的生物标志物。亚类、免疫细胞共刺激和代谢，并评估它们与 CVD 事件的关系；为了继续建立独立的研究计划，Olson 博士将在 R01 中开发和准备。 Tracy 博士是 CHS 和 MESA 核心实验室的主任，在 CVD 流行病学、炎症、 Tracy 博士目前拥有 16 个积极资助的合同和奖项，并主要参与多项国内和国际流行病学研究、临床研究和临床试验。奥尔森博士成功过渡到独立教职职位。