MODIFICATION OF CARDIOVASCULAR PROTEINS BY METABOLIC DISEASE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 在西方世界，不利的代谢状况和疾病，包括肥胖、糖尿病和高脂血症，是心血管疾病的主要原因，但对代谢性疾病对心脏和血管系统的不利影响的早期发现和监测仍然难以实现。炎症，氧化性 应激、脂质堆积增强以及心脏和血管中的脂质过氧化是舒张性心力衰竭、高血压、心脏和血管肥大、僵硬和功能障碍的根源。炎症的血浆蛋白指标确实会发生一些刻板的、非特异性的变化 氧化剂作为全身代谢性疾病的证据。我们的假设是，通过有针对性的蛋白质组学方法来检测代谢异常对蛋白质的影响，将大大提高检测代谢原因引起的心血管疾病的特异性。该项目利用了我们的发现，即在患有肺动脉高压或系统性淀粉样病的患者的血浆蛋白质上发生了多个共价氧化和反应性脂质和糖基化修饰；这些结果是如何在病变组织中或对全身代谢变化做出反应时，血液成分如何成为“无辜的路人”的例子。我们的目标是通过检查病变心脏和血管系统中的哪些蛋白质被修改以及哪些修改是针对代谢性疾病发生的来改进这一方法，然后识别血浆中这些修改的蛋白质的子集，这些修改的蛋白质子集显示出作为疾病的组织特异性生物标志物的潜力。为了完成这些任务，我们正在继续开发和完善我们在过去七年中在NIH/NHLBI支持的BUSM-心血管蛋白质组中心核心实验室建立的蛋白质组管道和生物信息学工具。我们首先在人类代谢性疾病的小鼠模型中量化心脏和血管组织蛋白的丰度和修饰的变化，然后评估类似变化在人类群体中的发生，特别是妇女和黑人，他们面临着因代谢性疾病而发生心力衰竭的风险或容易受到影响。这项研究的预期结果将是一组代谢功能障碍的标志物，它们应该作为代谢综合征所致心血管功能障碍发生的候选早期生物标志物，以及用于检测和量化关键候选对象的成熟抗体和MS/MS方法。这些应该为检测和监测代谢性心血管疾病提供新的和强大的方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Unfavorable metabolic conditions and diseases, including obesity, diabetes, and hyperlipidemia, are major causes for cardiovascular disease in the Western world, and yet the early detection and monitoring of the adverse effects of metabolic disease on the heart and vasculature remain elusive. Inflammation, oxidative stress, enhanced accumulation of lipids, and lipid peroxidation in the heart and vasculature are at the root of diastolic heart failure, hypertension, and cardiac and vascular hypertrophy, stiffening, and dysfunction. Somewhat stereotypical, nonspecific changes do occur in plasma protein indicators of inflammation and oxidants as evidence of systemic metabolic disease. It is our hypothesis that the specificity of detecting cardiovascular disease of metabolic causes will be greatly increased by a targeted proteomic approach to detect the effects of abnormal metabolism on proteins. This project takes advantage of our discoveries that multiple covalent oxidative and reactive lipid and glycation modifications occur on plasma proteins in patients with pulmonary hypertension or with systemic amyloid disease; these results serve as examples of how blood components can be "innocent passersby," modified in diseased tissue or in response to systemic metabolic changes. Our goal is to refine this approach by examining which proteins within the diseased heart and vasculature are modified and what modifications occur in response to metabolic disease, and then to identify a subset of these modified proteins in the plasma that show potential for use as tissue-specific biomarkers of the disease. To accomplish these tasks, we are continuing to develop and refine the proteomics pipeline and bioinformatics tools that we built over the last seven years in the Core Laboratory of the NIH/NHLBI-supported BUSM-Cardiovascular Proteomics Center. We are first quantifying changes in the abundances and modifications of heart and vascular tissue proteins in mouse models of human metabolic disease and then assess the occurrence of similar changes in the human population, in particular women and Blacks, which is at risk for or subject to heart failure as a consequence of metabolic disease. The expected results of the this research will be a set of markers of metabolic dysfunction that should serve as candidate early biomarkers for the development of cardiovascular dysfunction as a result of metabolic syndromes, as well as proven antibody and MS/MS methods for the detection and quantification of the key candidates. These should provide new and powerful approaches to the detection and monitoring of metabolic cardiovascular disease.