Multi-scale systems analysis of blood pressure control and hypertension

摘要 这项拟议的项目通过以下方式研究高血压的潜在机制： 进行心血管表型通路相互作用的系统研究(在动物模型中 和病人)。高血压和高血压病是复杂的全身综合症，不太可能 根据单一原因/单一结果关系有效地理解。我们建议其中一个 理解这些系统相互作用的主要障碍是无法制定系统级别的 以产生可通过实验检验的预测的方式的假设。使用系统方法分析和 我们的研究团队已经开始解释分子、细胞、组织、器官和器官系统的数据 了解心血管表型和多因素本质的变革性进展 心血管疾病。我们开发了心血管系统各组成部分的多尺度模型 负责从一次又一次的心血管动力学到血液的长期调节的过程 音量。使用这些模型，我们已经确定并测试了关于两者之间关系的新假设 血管力学，自主神经功能，肾功能，动脉压，以及机械- 高血压病中的能量偶联。 在拟议的项目中，我们将在这些研究的基础上，探索和确定 自发性高血压和Dahl盐敏感大鼠模型的复杂心血管表型 高血压。在AIMS 1和AIMS 2中，将应用一组表型方案来探测心血管功能 在这两个免费赠送的啮齿动物模型(和相关的对照)期间，高血压的发展。 这些研究的数据将用计算模型进行分析，以：(I)确定现有的 假设能够解释实验模型中的观察结果，并可能被排除；(Ii) 确定需要对现有假设进行哪些修订/改进才能潜在地解释数据； 确定现有假说和新假说中潜在的相互依赖关系；最后(Iv)设计实验以 排除相互竞争的假设。在目标3下，我们将把从动物研究中学到的东西应用到设计中。 在临床上更好地诊断高血压的新方法，将基本发现和相关 未来在精确医学和定量系统药理学中应用的计算机模型。

Abstract This proposed project investigates the mechanisms underlying 'essential' (or 'primary') hypertension by undertaking a systems investigation of pathway interactions in cardiovascular phenotypes (in animal models and patients). Hypertension and hypertensive disease are complex whole body syndromes that are unlikely to be effectively understood in terms of single-cause/single-effect relationships. We propose that one of the central barriers to understanding these systems interactions has been an inability to formulate system-level hypotheses in ways that yield experimentally testable predictions. Using systems approaches to analyzing and interpreting molecular, cellular, tissue, organ, and organ-system data our research team has begun to make transformational progress on understanding the multifactorial nature of cardiovascular phenotype and cardiovascular disease. We have developed multi-scale models of components of the cardiovascular system responsible for processes ranging from beat-to-beat cardiovascular dynamics to long-term regulation of blood volume. Using these models, we have identified and tested new hypotheses on the relationship between vascular mechanics, autonomic function, renal function, arterial pressure, and the derangement of mechanical- energetic coupling in hypertensive disease. In the proposed project we will build on these studies to probe and identify the mechanisms underlying the complex cardiovascular phenotypes of the spontaneously hypertensive and Dahl salt sensitive rat models of hypertension. In Aims 1 and 2 a panel of phenotyping protocols will be applied to probe cardiovascular function in these two complimentary rodent models (and relevant controls) during the development of hypertension. Data will from these studies will be analyzed with computational models to: (i.) determine which existing hypotheses are able to explain the observations in the experimental models and which may be ruled out; (ii.) determine what revisions/refinements to existing hypotheses are needed to potentially explain the data; (iii) identify potential inter-dependencies in existing and novel hypotheses; and finally (iv.) to design experiments to rule out competing hypotheses. Under Aim 3 we will apply what we learn from the animal studies to design new ways to better diagnose hypertension in the clinic, translating the basic discoveries and associated computer models for future applications in precision medicine and quantitative systems pharmacology.