Multi-scale systems analysis of blood pressure control and hypertension

血压控制和高血压的多尺度系统分析

基本信息

批准号：
10117280
负责人：
DANIEL A BEARD
金额：
$ 50.2万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10117280
关键词：
Accounting Age Animal Model Animals Automobile Driving Biological Models Blood Vessels Blood Volume Cardiovascular Diseases Cardiovascular Models Cardiovascular Physiology Cardiovascular system Clinic Clinical Complex Computer Models Coupling Dahl Hypertensive Rats Data Data Analyses Dependence Development Diagnosis Diagnostic Disease Endocrine Essential Hypertension Experimental Models Functional disorder Future Genetic Models Genetic Predisposition to Disease Goals Heart Rate Heart failure Human Hypertension Inbred SHR Rats Individual Investigation Kidney Knowledge Learning Measurement Mechanics Modeling Molecular Morbidity - disease rate Natural History Nature Pathway interactions Patients Pharmacology Phenotype Physiological Prevalence Process Property Protocols documentation Rat Strains Rattus Regulation Regulatory Pathway Renal function Renin-Angiotensin System Research Rodent Model Sodium Chloride Sodium-Restricted Diet Syndrome System Systems Analysis Testing Therapeutic Intervention Tissues Translating Uncertainty autonomic reflex base blood pressure regulation body system cohort computer framework design disease phenotype experimental study global health heart function human data human subject hypertension treatment hypertensive heart disease improved in vivo knowledge base male mortality risk multi-scale modeling novel novel diagnostics novel therapeutic intervention phenotypic data precision medicine predictive modeling pressure response salt intake salt sensitive simulation solute translational study treatment strategy

项目摘要

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.

抽象的该提议的项目调查了“必需”（或“主要”）高血压的基础机制对心血管表型中的途径相互作用进行系统调查（在动物模型中和病人）。高血压和高血压疾病是复杂的全身综合征，不太可能有效地从单原因/单效关系方面有效理解。我们建议其中之一理解这些系统互动的主要障碍是无法制定系统级的假设以实验测试预测的方式产生。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，我们的研究团队已开始使理解心血管表型的多因素性质的变革进步和心血管疾病。我们开发了心血管系统组件的多尺度模型负责从节拍到基础性心血管动力学到长期血液调节的过程体积。使用这些模型，我们已经确定并检验了有关关系的新假设血管力学，自主功能，肾功能，动脉压以及机械的毁灭高血压疾病中的能量耦合。在拟议的项目中，我们将以这些研究为基础，以探测和确定该研究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，将应用一组表型方案来探测心血管功能在这两个免费的啮齿动物模型（和相关控制）中，高血压发育。这些研究将通过计算模型分析：（i。）确定现有的数据假设能够解释实验模型中的观察结果，并可以排除在外。（ii。）确定需要对现有假设进行哪些修订/改进来说明数据；（iii）确定现有和新颖假设中潜在的相互依赖性；最后（iv。）设计实验排除竞争假设。在AIM 3下，我们将应用我们从动物研究中学到的知识来设计在诊所中更好地诊断高血压的新方法，转化基本发现和相关的用于未来应用的计算机模型，用于精密医学和定量系统药理学。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure.

DOI：
10.1161/circulationaha.122.059486
发表时间：
2022-05-24
期刊：
CIRCULATION
影响因子：
37.8
作者：
Borlaug, Barry A.;Blair, John;Bergmann, Martin W.;Bugger, Heiko;Burkhoff, Dan;Bruch, Leonhard;Celermajer, David S.;Claggett, Brian;Cleland, John G. F.;Cutlip, Donald E.;Dauber, Ira;Eicher, Jean-Christophe;Gao, Qi;Gorter, Thomas M.;Gustafsson, Finn;Hayward, Chris;van der Heyden, Jan;Hasenfuss, Gerd;Hummel, Scott L.;Kaye, David M.;Komtebedde, Jan;Massaro, Joseph M.;Mazurek, Jeremy A.;McKenzie, Scott;Mehta, Shamir R.;Petrie, Mark C.;Post, Marco C.;Nair, Ajith;Rieth, Andreas;Silvestry, Frank E.;Solomon, Scott D.;Trochu, Jean-Noel;Van Veldhuisen, Dirk J.;Westenfeld, Ralf;Leon, Martin B.;Shah, Sanjiv J.
通讯作者：
Shah, Sanjiv J.

Salt Taste Sensitivity and Heart Failure Outcomes Following Heart Failure Hospitalization.

心力衰竭住院后的盐味敏感性和心力衰竭结果。