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

 描述(由申请人提供)：这是为艾默里大学心力衰竭(HF)和移植心脏病专家Alanna Morris博士申请K23奖项，她的职业生涯是一名年轻的研究员，从事面向患者的临床和转化研究。这一K23奖项将为Morris博士发展独立的临床研究生涯提供必要的支持，这些支持将确立她在以下方面的专长：(1)以患者为导向的转化性研究I心力衰竭严重程度的潜在机制，包括生物标记物、代谢组学分析和血管功能的非侵入性评估；(2)这些机制中的种族差异，以阐明导致心力衰竭风险的种族差异的生物途径；(3)通过攻读临床研究理学硕士学位，在临床研究中应用先进的生物统计学方法；以及(4)发展独立的临床研究事业。为了实现这些目标，莫里斯博士组建了一个指导团队，成员包括一位主要导师、埃默里临床心血管研究所联席主任阿希德·奎尤米博士，他的研究开创了对血管功能进行有创和非侵入性评估的先河；以及三位导师：贾维德·巴特勒博士，埃默里大学心力衰竭研究的前主任，最近被任命为 纽约大学斯坦布鲁克分校心脏病学；Dean Jones博士，Emory临床生物标记物主任 他是一位专注于氧化应激生物标记物和高通量临床代谢组学研究的实验室专家；以及在高通量代谢组学方法领域拥有最先进生物统计和生物信息学方法专长的于天伟博士。 尽管在过去的几十年里，心力衰竭的治疗有所改善，但患有心力衰竭的患者和 射血分数(HFrEF)是临床预后不良的高危因素，包括死亡和住院。 此外，黑人患者患心力衰竭的年龄较小，入院治疗和死亡的风险更高。氧化应激(OS)在心力衰竭的进展中起着重要作用，我们的研究将探讨一氧化氮(NO)与OS之间的相互作用，即亚硝基-氧化还原平衡，是如何在心力衰竭恶化的病理生理过程中起作用的。增加OS会扰乱NO信号，导致内皮功能障碍和血管僵硬，从而增加衰竭心脏的工作量。我们先前的数据表明，与白人相比，黑人的OS水平更高，NO的生物利用度更低，血管功能受损。尽管不利的亚硝基-氧化还原平衡和血管功能受损可能是黑人体内观察到的过量HF的原因之一，但这一理论尚未得到证实。此外，代谢组学分析是一种创新的方法，可以用来发现涉及心力衰竭发病机制的新的分子途径，从而识别新的诊断标记和治疗靶点。我们的研究计划试图全面检查HFrEF患者的亚硝基-氧化还原平衡、血管功能和代谢物之间的关系，并确定这些预测因素中的种族差异是否会导致在这一人群中观察到的过量心力衰竭风险。在目标1中，我们将确定全身性亚硝基-氧化还原平衡的生物标志物是否与临床心力衰竭相关事件(HFRE)相关，包括一年内的死亡率、住院和急诊科就诊。在目标2中，我们将验证评估血管功能的新方法，包括外周和放射状动脉测压，与现有方法(如血流介导的扩张)相比，是否可以预测HFRE。在目标3中，我们将进行一项代谢性关联研究，以确定心力衰竭严重程度的候选代谢物，并使用计算和生物信息学工具将这些代谢物映射到代谢谱。对于每个目标，我们将具体检查测量的标记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果种族差异的潜在生物学机制。 我们计划执行这项拟议的研究，作为为期5年的K23职业发展奖的一部分，该奖项将增强莫里斯博士作为独立临床医生兼科学家的能力。莫里斯医生的 先前检查OS和血管功能的黑白差异的研究经验为在HFrEF患者中进行拟议的研究提供了坚实的基础，因为OS越来越多地与HF的病理生理学有关。杰出的导师和合作导师小组将提供技术和智力指导，而K23奖项将提供受保护的研究时间和教学教育机会。此外，Emory参与了亚特兰大临床转化科学研究所(ACTSI)，其中包括由NIH资助的临床研究网络(CRN)，该网络为Morris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，以实施她的研究提案。莫里斯博士将完成临床研究理学硕士学位，接受生物统计学和临床研究设计方面的正式培训。K23奖项将帮助莫里斯博士实现她在翻译和健康差异研究方面取得成功的长期目标，为了解1)亚硝基-氧化还原平衡的种族差异及其对心力衰竭患者种族差异的影响做出科学贡献，以及2)生物标记物和血管概况有助于HFrEF患者的风险预测模型。

 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.