ADDRESSING THE CONTINUING CHALLENGE OF IDENTIFYING AND MANAGING CORONARY RISK: A PERSON-SPECIFIC STRATEGY USING PROTEOMICS

应对识别和管理冠状动脉风险的持续挑战：利用蛋白质组学的个体化策略

• 批准号: 10549983
• 负责人: Spiros D. Garbis
• 金额: $ 29.52万
• 依托单位: PROTEAS BIOANALYTICS INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10549983
• 关键词: Address; Age; Algorithms; American; Arginine; Assessment tool; Atherosclerosis; Biochemical Reaction; Biological Factors; Blood; Blood Pressure; Blood Tests; Blood Vessels; Body fat; Businesses; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cells; Clinical; Collaborations; Coronary; Coronary Arteriosclerosis; Coronary artery; Coronary heart disease; Data; Development; Diagnosis; Dimensions; Dyslipidemias; Effectiveness; Effectiveness of Interventions; Endothelial Cells; Endothelium; Event; Exercise; Functional disorder; Goals; Gold; Human; Hypertension; Imaging technology; Individual; Inflammation; Intervention; Isometric Exercise; Laboratories; Life Style; Magnetic Resonance Imaging; Measures; Mediating; Modification; Myocardial Infarction; NOS3 gene; National Heart, Lung, and Blood Institute; Nitric Oxide; Nitric Oxide Signaling Pathway; Nitric Oxide Synthase; Outcome; Outcome Measure; Oxidative Stress; Participant; Pathway interactions; Persons; Phase; Phosphorylation; Physical activity; Plasma; Plasma Cells; Post-Translational Protein Processing; Prevention; Process; Proteins; Proteomics; Provider; Psyche structure; Public Health; Research; Residual state; Risk; Risk Assessment; Risk Factors; Role; Safety; Signal Transduction; Site; Sleep; Small Business Innovation Research Grant; Soluble Guanylate Cyclase; Specimen; Stimulus; Stress; Technology; Testing; TimeLine; Validation; Vascular Diseases; base; cardiac magnetic resonance imaging; cardiovascular risk factor; cell behavior; clinical practice; clinical risk; clinically relevant; commercialization; coronary event; coronary vasculature; disorder risk; experience; imaging study; improved; indexing; innovation; mortality; new technology; novel; personalized intervention; preempt; preventive intervention; programs; proteomic signature; response; success; tetrahydrobiopterin; therapy design; tool

Project Summary/Abstract: Despite considerable advances in the prevention and management of coronary disease (CAD), several hundred thousand Americans experience myocardial infarctions each year. One reason is that current clinical risk assessment does not encompass many residual risk factors, e.g. oxidative stress. Endothelial-dependent coronary vascular dysfunction is a “final common pathway” for many of these, as well as for Framingham established, risk factors. Coronary vascular dysfunction is also a driver of atherosclerosis. Despite its critical role, the technology to assess this function is not widely available, as it requires measures of coronary flow before and during an endothelial-dependent stimulus. One key goal of the NHLBI is to advance the prediction, prevention, preemption, treatment, and cures of cardiovascular diseases. Our proposal is aimed towards commercial development of a clinically available blood test indicative of coronary vascular function, which would advance person-specific assessment of CAD risk and the ability of an intervention to decrease that risk. Proteas Bioanalytics, a small business concern, and Johns Hopkins aim to discover plasma and cell proteomic signatures that closely correlate with function of the coronary vasculature, the clinically relevant site of CAD events. The Johns Hopkins team has demonstrated that cardiac magnetic resonance imaging (MRI) measured increases in coronary flow following initiation of isometric handgrip exercise is dependent on an endothelial nitric oxide synthase mediated increase in nitric oxide (NO). The adverse impact of risk factors could therefore be attributed to changes in the concentrations and/or activities of NO synthase substrates (e.g. l-arginine), co-factors (e.g. tetrahydrobiopterin), activity (phosphorylation), and/or downstream products (e.g. soluble guanylyl cyclase). The Proteas Bioanalytics team developed a state-of-the-art platform capable of plasma and single cell proteomics analysis. We aim to use this technology to measure NO related pathways and eventually discover an algorithm describing which one or combination of pathway factors best correlate with MRI-determined coronary vascular function. Our specific aims for this SBIR Phase One study are: 1) To demonstrate the feasibility and technical ability of Johns Hopkins to perform MRI studies of coronary endothelial function in subjects with and without CAD and hence varying degrees of coronary vascular function and to collect biospecimens from these participants for subsequent proteomic analysis. 2) To demonstrate the feasibility and technical ability of Proteas Bioanalytics to analyze the biospecimens obtained from the participants studied in the first aim and identify plasma and cell proteins related to coronary vascular function. If successful, the results will support a subsequent SBIR Phase Two/Three program to develop a plasma and cell proteomic “signature” that characterizes coronary vascular function. If achieved, the small business concern could then market a clinically available and effective blood test to enhance the person-specific assessment of coronary risk and the ability of an intervention to decrease that risk for hundreds of millions of Americans.

项目摘要/摘要： 尽管冠心病 (CAD) 的预防和管理取得了相当大的进步，但仍有数百名 每年有数千名美国人经历心肌梗塞，原因之一是当前的临床风险。 评估不包括许多残余危险因素，例如内皮依赖性。 冠状血管功能障碍是其中许多人以及弗雷明汉的“最终共同途径” 已确定，冠状血管功能障碍也是动脉粥样硬化的一个驱动因素。 评估此功能的技术尚未广泛使用，因为它需要在之前测量冠状动脉流量 在内皮依赖性刺激期间，NHLBI 的一个关键目标是推进预测， 我们的建议旨在预防、预防、治疗和治愈心血管疾病。 临床可用的冠状血管功能血液检测指标的商业开发，这将 推进针对 CAD 风险的个人评估以及降低该风险的干预措施的能力。 生物分析是一家小型企业，它和约翰霍普金斯大学的目标是发现血浆和细胞蛋白质组学特征 与冠状动脉血管系统的功能密切相关，冠状动脉血管系统是 CAD 事件的临床相关部位。 约翰·霍普金斯大学团队证明，心脏磁共振成像 (MRI) 测量到的 开始等长握力运动后的冠状动脉流量取决于内皮一氧化氮 因此，危险因素的不利影响可归因于合成酶介导的一氧化氮（NO）增加。 NO合酶底物（例如L-精氨酸）、辅助因子（例如L-精氨酸）浓度和/或活性的变化 四氢生物蝶呤）、活性（磷酸化）和/或下游产物（例如可溶性鸟苷酸环化酶）。 Proteas Bioanalytics 团队开发了最先进的血浆和单细胞蛋白质组学平台 我们的目标是利用这项技术来测量 NO 相关路径并最终发现一种算法。 描述与 MRI 确定的冠状血管最相关的一种途径因素或途径因素组合 我们进行 SBIR 第一阶段研究的具体目标是： 1) 论证可行性和技术性。 约翰·霍普金斯大学对患有以下疾病的受试者进行冠状动脉内皮功能 MRI 研究的能力 没有 CAD，因此有不同程度的冠状血管功能，并从 2）论证可行性和技术性 Proteas Bioanalytics 分析从研究参与者获得的生物样本的能力 首先目标是识别与冠状血管功能相关的血浆和细胞蛋白。 结果将支持随后的 SBIR 第二/第三阶段计划，以开发血浆和细胞蛋白质组学 如果实现了表征冠状血管功能的“特征”，那么小型企业就可以实现这一目标。 营销临床可用且有效的血液检测，以加强对冠状动脉风险的个体化评估 以及干预措施降低数亿美国人面临的风险的能力。