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

项目概要/摘要： 尽管在预防和管理冠状动脉疾病（CAD）方面取得了相当大的进展，但仍有数百例患者在接受治疗。 每年有数千美国人经历心肌梗塞。一个原因是目前的临床风险 评估不包括许多剩余风险因素，例如氧化应激。内皮依赖 冠状动脉血管功能障碍是其中许多人的“最终共同途径”， 建立风险因素。冠状动脉血管功能障碍也是动脉粥样硬化的驱动因素。尽管它的关键作用， 评估这一功能的技术还没有广泛使用，因为它需要测量冠状动脉血流， 以及在内皮依赖性刺激期间。NHLBI的一个关键目标是推进预测， 心血管疾病的预防、预防、治疗和治愈。我们的建议旨在 临床上可用的指示冠状血管功能的血液测试的商业开发，其将 先进的CAD风险的个人特定评估和干预措施降低风险的能力。Proteas 生物分析，一个小企业的关注，和约翰霍普金斯旨在发现血浆和细胞蛋白质组签名 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。的 约翰霍普金斯研究小组已经证明，心脏磁共振成像（MRI）测量的增加， 等长握力运动后冠状动脉血流依赖于内皮一氧化氮 合成酶介导的一氧化氮（NO）增加。因此，风险因素的不利影响可归因于 NO合酶底物（例如L-精氨酸）、辅因子（例如， 在一些实施方案中，活性（磷酸化）和/或下游产物（例如，可溶性鸟苷酸环化酶）的活性（例如，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）的活性。的 Proteas Bioanalytics团队开发了一个能够进行血浆和单细胞蛋白质组学的最先进平台 分析.我们的目标是使用这种技术来测量NO相关的通路，并最终发现一种算法， 描述哪一种或哪几种途径因素的组合与MRI确定的冠状动脉血管最相关 功能我们进行SBIR第一阶段研究的具体目标是：1）证明SBIR的可行性和技术 约翰霍普金斯对患有和 无CAD，因此冠状动脉血管功能程度不同，并从 这些参与者用于随后的蛋白质组学分析。2)为了证明可行性和技术 Proteas Bioanalytics分析从参与研究的参与者中获得的生物标本的能力 第一个目标是鉴定与冠状动脉血管功能相关的血浆和细胞蛋白。如果成功， 结果将支持随后的SBIR第二/三阶段计划，以开发血浆和细胞蛋白质组学 冠状动脉血管功能的特征。如果实现了，小企业就可以 推广临床可用的有效血液检测，以加强对冠心病风险的个人特定评估 以及干预措施降低数亿美国人风险的能力。

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.