Multi-scale systems analysis of blood pressure control and hypertension

摘要 本项目拟通过以下方法研究“原发性”（或“原发性”）高血压的机制： 进行心血管表型中通路相互作用的系统研究（在动物模型中 患者）。高血压和高血压病是复杂的全身综合征， 从单因/单果关系的角度有效理解。我们建议， 理解这些系统交互的主要障碍是无法制定系统级的 以产生实验可检验的预测的方式提出假设。使用系统方法分析和 解释分子，细胞，组织，器官和器官系统数据，我们的研究团队已经开始 在理解心血管表型的多因素性质方面取得了变革性进展， 心血管疾病我们已经开发了心血管系统组成部分的多尺度模型 负责从心跳到心跳的心血管动力学到长期血液调节的过程 音量.使用这些模型，我们已经确定并测试了新的假设之间的关系 血管力学、自主神经功能、肾功能、动脉压和机械- 高血压疾病中的能量耦合。 在拟议的项目中，我们将在这些研究的基础上探索和确定潜在的机制， 自发性高血压和Dahl盐敏感大鼠模型的复杂心血管表型 高血压在目标1和2中，将应用一组表型分析方案来探测心血管功能 在这两个补充啮齿动物模型（和相关对照）的高血压发展过程中。 这些研究的数据将通过计算模型进行分析，以：（i.）确定现有的 假设能够解释实验模型中的观察结果，并且可以排除;（ii.） 确定需要对现有假设进行哪些修订/改进，以潜在地解释数据;（iii） 识别现有和新假设中的潜在相互依赖性;以及最后（iv.）设计实验， 排除相互矛盾的假设在目标3下，我们将把我们从动物研究中学到的知识应用于设计 在临床上更好地诊断高血压的新方法，将基本发现和相关的 计算机模型，用于未来在精密医学和定量系统药理学中的应用。

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.