Spatial Analysis of Cardiac Disease using Murine Four-Dimensional Ultrasound

项目摘要/摘要 心脏可以说是人体最关键的器官之一，因为它驱动氧气的分配， 营养物质、信号因子和整个身体的热量。任何形式的心功能不全都可以 损害个人的寿命和生活质量；严重的病例会导致器官衰竭和死亡。根据 根据2017年美国心脏协会(AHA)的年度报告，心脏病仍然是导致心脏病的头号原因 美国的死亡案例。这一令人遗憾的统计数字突显了需要新的和创新的方法来 认识和治疗心脏病。为此，小鼠心脏病模型起到了至关重要的作用 在系统探索心脏病理生理学的复杂潜在机制方面的作用。不幸的是， 最常用的活体成像工具来测量这些小鼠的心脏功能，高频线性- 阵列超声在很大程度上依赖于左心室的理想化几何形状来估计功能指标。我们有 最近开发并验证了一种四维超声(4DUS)技术，该技术使用相同的 基础技术，但提供了代表心脏的小鼠心脏的体积信息 周而复始。遵循国家心肺血液研究所(NHBLI)设定的目标： 并优化新的诊断和治疗策略以预防、治疗和治愈HLBS疾病“和 随后提出了一个令人关注的问题：如何利用成像技术来识别临床上有用的 代谢综合征和心肺疾病的标志物？“，拟议的工作将以此为基础。 4DUS技术为研究人员创建了一个平台，以更多地评估他们模型中的心功能 全面高于标准心脏指标(例如跨壁应变、节段性心腔充盈/射血 图案等)并将这些测量结果与本地化的细胞水平信息相关联。我们计划完成 这一目标通过以下两个目标：1)完善和验证我们的4DUS分析软件，以提供可靠的 心脏运动学指标，可以在小鼠4DUS数据队列中进行强有力的比较；2)评估 三种不同心脏模型中局部应变和蛋白质组学特征之间的相关性 疾病。这一奖学金研究和培训将在普渡大学进行， 克雷格·戈尔根博士、王一文博士、杰西卡·埃利斯博士和毛罗·科斯塔博士的监督。这部作品用的是小说 方法学将导致我们对空间特异性代谢如何理解的巨大进步 先天性心脏病和心肌梗死小鼠模型的特征与心功能障碍相关 脑梗塞。进一步广泛采用该平台将提供一种可扩展的方法来研究 心脏病其他心脏模型的空间调节和增加NHBLI的科学覆盖面 研究社区。

PROJECT SUMMARY/ABSTRACT The heart is arguably one of the most critical organs of the human body as it drives the distribution of oxygen, nutrients, signaling factors, and heat throughout the entire body. Any form of cardiac dysfunction can thus compromise an individual’s longevity and quality-of-life; severe cases lead to organ failure and death. According to the 2017 American Heart Association (AHA) annual report, heart disease remains the number one cause of death in the United States. This unfortunate statistic highlights the need for new and innovative approaches to understanding and treating cardiac disease. To this end, murine models of cardiac disease have played a crucial role in systematically exploring the complex underlying mechanisms to cardiac pathophysiology. Unfortunately, the most commonly used in vivo imaging tool to measure heart function in these mice, high-frequency linear- array ultrasound, relies heavily on idealized geometries of the left-ventricle to estimate function metrics. We have recently developed and validated a four-dimensional ultrasound (4DUS) technique that uses this same underlying technology, but provides volumetric information of the murine heart across a representative cardiac cycle. Following in the objective set by the National Heart, Lung, and Blood Institute (NHBLI) to “develop and optimize novel diagnostic and therapeutic strategies to prevent, treat, and cure HLBS diseases” and subsequent Compelling Question “How can imaging technology be leveraged to identify clinically useful markers of metabolic syndrome and cardiopulmonary disease?”, the proposed work will build upon this 4DUS technique to create a platform for researchers to assess cardiac function in their models more comprehensively than standard cardiac metrics (e.g. transmural strain, segmented chamber filling/ejection patterns, etc.) and correlate those measurements to localized cellular-level information. We plan to accomplish this goal through the following two AIMS: 1) Refine and validate our 4DUS analysis software to provide reliable metrics of cardiac kinematics, which can be robustly compared across cohorts of murine 4DUS data; 2) Assess myocardial dysfunction by correlating regional strain and proteomic profiles in three separate models of cardiac disease. This fellowship research and training will be carried out at Purdue University under the thoughtful supervision of Drs. Craig Goergen, I-wen Wang, Jessica Ellis, and Mauro Costa. This work using novel methodologies will lead to enormous advancements in our understanding on how spatial specific metabolic profiles are associated with heart dysfunction in murine models of congenital heart disease and myocardial infarction. Further widespread adoption this platform will provide an expandable approach to study the role of spatial regulation in other cardiac models of heart disease and increase the scientific reach of the NHBLI research community.