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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.

抽象的该拟议项目通过以下方式研究“原发性”（或“原发性”）高血压的潜在机制对心血管表型中的通路相互作用进行系统研究（在动物模型中和患者）。高血压和高血压疾病是复杂的全身综合征，不太可能根据单因/单果关系得到有效理解。我们建议其中一项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可通过实验检验的预测的方式提出假设。使用系统方法来分析和我们的研究团队已经开始解释分子、细胞、组织、器官和器官系统数据在理解心血管表型和多因素性质方面取得的变革性进展心血管疾病。我们开发了心血管系统组成部分的多尺度模型负责从逐次心跳的心血管动力学到血液的长期调节等过程体积。使用这些模型，我们已经确定并测试了关于之间关系的新假设血管力学、自主神经功能、肾功能、动脉压和机械紊乱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达尔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高血压发展过程中，这两种互补的啮齿动物模型（和相关对照）。来自这些研究的数据将通过计算模型进行分析，以：（i.）确定哪些现有的假设能够解释实验模型中的观察结果并且可以被排除；（二）确定需要对现有假设进行哪些修改/完善才能解释数据； (三) 确定现有和新假设中潜在的相互依赖性；最后 (iv.) 设计实验排除相互竞争的假设。在目标 3 下，我们将应用从动物研究中学到的知识来设计在临床上更好地诊断高血压的新方法，转化了基本发现和相关未来在精准医学和定量系统药理学中应用的计算机模型。

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。