Metabolomics, Oxidative Stress, and Vascular Function in Heart Failure Patients

心力衰竭患者的代谢组学、氧化应激和血管功能

• 批准号: 9521518
• 负责人: Alanna Amyre Morris
• 金额: $ 16.76万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-16 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9521518
• 关键词: Affect; Age; American; Biochemical; Bioinformatics; Biological Assay; Biological Availability; Biological Markers; Biometry; Biostatistical Methods; Blood Vessels; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Characteristics; Clinical; Clinical Research; Complement; Data; Detection; Diagnosis; Dilatation - action; Discipline of Nursing; Disease; EFRAC; Emergency department visit; Epidemiology; Equilibrium; Event; Foundations; Frequencies; Functional disorder; Funding; Goals; Health Services Accessibility; Heart; Heart Transplantation; Heart failure; Hospitalization; Human; Hybrids; Impairment; Incidence; Institutes; Isoprostanes; K-Series Research Career Programs; Laboratories; Left ventricular structure; Maps; Master of Science; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Metabolic Pathway; Metabolism; Methods; Molecular; Myocardial dysfunction; Nitric Oxide; Outcome; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Pathway; Pathogenesis; Pathway interactions; Patients; Peripheral; Phenotype; Physiology; Plasma; Play; Population; Population Study; Race; Radial; Research; Research Design; Research Institute; Research Personnel; Research Proposals; Resolution; Risk; Role; Scientist; Severities; Severity of illness; Signal Transduction; Statistical Data Interpretation; Supervision; Techniques; Testing; Time; Training; Translational Research; United States National Institutes of Health; Universities; Up-Regulation; Vascular Diseases; Work; Workload; aminothiol; arterial stiffness; arterial tonometry; biobank; cardiovascular risk factor; career; clinical biomarkers; clinical predictors; cohort; diagnostic biomarker; didactic education; endothelial dysfunction; equilibration disorder; experience; health disparity; high risk; hospitalization rates; indexing; innovation; metabolic profile; metabolome; metabolomics; mortality; novel; novel diagnostics; patient oriented; predictive modeling; prospective; public health relevance; racial difference; racial disparity; recruit; theories; therapeutic target; tool

 DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Alanna Morris, a heart failure (HF) and transplant cardiologist at Emory University who is beginning her career as a young investigator in patient-oriented clinical and translational research. This K23 award will provide Dr. Morris with the support necessary to develop an independent clinical research career that will establish her expertise in: (1) patient-oriented translational research i mechanisms underlying HF disease severity, including biomarkers, metabolomics analysis, and non-invasive assessments of vascular function; (2) racial differences in these mechanisms to elucidate biologic pathways underlying racial disparities in HF risk; (3) to implement advanced biostatistical methods in clinical studies by pursuing a Master of Science in Clinical Research; and (4) to develop an independent clinical research career. To achieve these goals, Dr. Morris has assembled a mentoring team comprised of a primary mentor, Dr. Arshed Quyyumi, Co-Director of the Emory Clinical Cardiovascular Research Institute whose research has pioneered the use of invasive and noninvasive assessments of vascular function; and three mentors: Dr. Javed Butler, former Director of HF Research at Emory and recently appointed Chief of Cardiology at University of NY-Stonybrook; Dr. Dean Jones, Director of the Emory Clinical Biomarkers Laboratory whose work focuses on biomarkers of oxidative stress and high-throughput clinical metabolomic profiles; and Dr. Tianwei Yu, who has expertise in state-of-the-art biostatistic and bioinformatics methods in high-throughput metabolomics methods. Despite improvements in the treatment of HF in the past few decades, patients with HF and reduced ejection fraction (HFrEF) are at high risk for poor clinical outcomes, including death and hospitalization. Furthermore, Black patients develop HF at younger ages and are at higher risk for HF hospitalizations and death. Oxidative stress (OS) plays an important role in HF progression, and our research will examine how the interaction between nitric oxide (NO) and OS, termed the nitroso-redox balance, contributes to the pathophysiology of worsening HF. Increasing OS disrupts NO signaling, inducing endothelial dysfunction and vascular stiffness that augment the workload for the failing heart. Our prior data suggest that Blacks have higher levels of OS, lower NO bioavailability, and impaired vascular function as compared to Whites. Although unfavorable nitroso-redox balance and impaired vascular function may contribute to the excess HF observed in Blacks, this theory has not been proven. In addition, analysis of metabolomics profiles is an innovative method that can be utilized to discover new molecular pathways involved in the pathogenesis of heart failure, and hence the identification of novel diagnostic markers and therapeutic targets. Our research plan seeks to comprehensively examine the association of nitroso-redox balance, vascular function, and metabolites in patients with HFrEF, and identify whether racial differences in these predictors contribute to the excess HF risk observed in this population. In Aim 1, we will determine if biomarkers of systemic nitroso-redox balance are associated with clinical HF related events (HFRE), including mortality, hospitalizations, and emergency department visits at one year. In Aim 2, we will verify if novel methods of assessing vascular function, including peripheral and radial arterial tonometry, predict HFRE compared to established methods such as flow-mediated dilatation. In Aim 3, we will perform a metabolomewide association study to identify candidate metabolites characteristic of heart failure severity, and use computational and bioinformatic tools to map these to metabolic profiles. For each Aim, we will specifically examine if there are racial differences in the measured markers, to determine potential biologic mechanisms for observed racial disparities in heart failure severity and clinical outcomes. We plan to execute the proposed research as part of a 5-year K23 career development award that will enhance Dr. Morris' ability to operate as an independent clinician-scientist. Dr. Morris' prior research experience examining Black-White differences in OS and vascular function provide a strong foundation for performing the proposed research in patients with HFrEF, as OS is increasingly implicated in the pathophysiology of HF. The exceptional group of mentors and co-mentors will provide both technical and intellectual supervision, while the K23 award will provide the opportunity for protected research time and didactic education. Moreover, Emory's participation in the Atlanta Clinical Translational Science Institute (ACTSI) includes a NIH-funded Clinical Research Network (CRN) that offers Dr. Morris a full complement of nursing, core laboratory support, and bioinformatics and statistical analysis to carry out her research proposal. Dr. Morris will complete a Master's of Science in Clinical Research, giving her formal training in biostatistics and clinical research design. The K23 award will help Dr. Morris achieve her long-term goal of having a successful career in translational and health disparities research, making scientific contributions to the understanding of 1) racial differences in nitroso-redox balance and its impact on racial disparities in HF, and 2) biomarkers and vascular profiles to aid in risk prediction models for HFrEF patients.

 描述（由申请人提供）：这是一个K23奖的阿兰娜莫里斯博士，心力衰竭（HF）和移植心脏病专家在埃默里大学谁是开始她的职业生涯作为一个年轻的研究者在以病人为导向的临床和转化研究的应用。该K23奖项将为Morris博士提供发展独立临床研究职业生涯所需的支持，这将建立她在以下方面的专业知识：（1）以患者为导向的转化研究，即HF疾病严重程度的相关机制，包括生物标志物、代谢组学分析和无创评估血管功能;（2）这些机制的种族差异，以阐明HF风险种族差异的生物学途径;（3）修读临床研究理学硕士课程，在临床研究中应用先进的生物统计方法;及（4）发展独立的临床研究事业。为了实现这些目标，Morris博士组建了一个指导团队，由一名主要导师Arshed Quyyumi博士和三名导师组成，Arshed Quyyumi博士是埃默里临床心血管研究所的联合主任，他的研究开创了血管功能有创和无创评估的使用，Javed Butler博士是埃默里HF研究的前主任，最近被任命为埃默里心脏病研究中心主任。 纽约大学斯托尼布鲁克分校心脏病学; Dean Jones博士，埃默里临床生物标志物主任 实验室，其工作重点是氧化应激和高通量临床代谢组学谱的生物标志物;以及Tianwei Yu博士，他在高通量代谢组学方法中拥有最先进的生物统计学和生物信息学方法的专业知识。 尽管在过去的几十年里，HF的治疗有所改善，但HF患者的死亡率降低， 射血分数（HFrEF）的高风险的不良临床结果，包括死亡和住院治疗。 此外，黑人患者在较年轻时发生HF，并且HF住院和死亡的风险较高。氧化应激（OS）在HF进展中起着重要作用，我们的研究将探讨一氧化氮（NO）和OS之间的相互作用，称为亚硝基氧化还原平衡，有助于HF恶化的病理生理学。增加OS破坏NO信号传导，诱导内皮功能障碍和血管僵硬，增加衰竭心脏的工作负荷。我们以前的数据表明，黑人有较高水平的OS，较低的NO生物利用度，和受损的血管功能相比，白人。虽然不利的亚硝基-氧化还原平衡和受损的血管功能可能有助于在黑人中观察到的过量HF，但这一理论尚未得到证实。此外，代谢组学谱分析是一种创新方法，可用于发现心力衰竭发病机制中涉及的新分子途径，从而鉴定新的诊断标志物和治疗靶点。我们的研究计划旨在全面检查HFrEF患者的亚硝基氧化还原平衡、血管功能和代谢物的相关性，并确定这些预测因子的种族差异是否有助于在该人群中观察到的HF风险过高。在目标1中，我们将确定全身亚硝基-氧化还原平衡的生物标志物是否与临床HF相关事件（HFRE）相关，包括一年内的死亡率、住院率和急诊就诊率。在目标2中，我们将验证评估血管功能的新方法，包括外周动脉和桡动脉张力测定，与已建立的方法（如流量介导的扩张）相比，是否可预测HFRE。在目标3中，我们将进行代谢组关联研究，以确定心力衰竭严重程度的候选代谢物特征，并使用计算和生物信息学工具将其映射到代谢谱。对于每个目标，我们将专门检查测量的标志物是否存在种族差异，以确定观察到的心力衰竭严重程度和临床结局种族差异的潜在生物学机制。 我们计划执行拟议的研究作为5年K23职业发展奖的一部分，这将提高莫里斯博士作为独立临床科学家的能力。莫里斯医生的 检查OS和血管功能的黑白差异的先前研究经验为在患有HFrEF的患者中进行所提出的研究提供了强有力的基础，因为OS越来越多地涉及HF的病理生理学。导师和共同导师的特殊群体将提供技术和智力监督，而K23奖将提供受保护的研究时间和教学教育的机会。此外，埃默里大学在亚特兰大临床转化科学研究所（ACTSI）的参与包括NIH资助的临床研究网络（CRN），为莫里斯博士提供全面的护理，核心实验室支持，生物信息学和统计分析，以执行她的研究计划。Morris博士将完成临床研究理学硕士学位，在生物统计学和临床研究设计方面接受正式培训。K23奖将帮助Morris博士实现她在转化和健康差异研究方面取得成功的长期目标，为理解1）亚硝基氧化还原平衡的种族差异及其对HF种族差异的影响做出科学贡献，以及2）生物标志物和血管概况，以帮助HFrEF患者的风险预测模型。