Modeling Multiscale Immuno-Mechanics in Aortic Disease

主动脉疾病的多尺度免疫力学建模

• 批准号: 10532786
• 负责人: Jay D. Humphrey
• 金额: $ 49.18万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532786
• 关键词: Address; Adolescent; Age of Onset; Animal Model; Anti-Inflammatory Agents; Antihypertensive Agents; Aorta; Aortic Diseases; Arteries; Biological; Biology; Biomechanics; Blood; Blood Vessels; Caliber; Cardiovascular Physiology; Cardiovascular system; Cells; Cessation of life; Child; Clinical; Collaborations; Combination Drug Therapy; Complement; Computer Models; Coupled; Data; Data Set; Databases; Development; Disease; Disease Progression; Endothelial Cells; Ensure; Environment; Epidemic; Extracellular Matrix Degradation; Fibroblasts; Foundations; Gene Expression; Geometry; Goals; Homeostasis; Hypertension; Immune; Immunologics; Inflammation; Inflammatory; Lead; Macrophage; Mathematics; Mechanical Stress; Mechanics; Modeling; Molecular; Morbidity - disease rate; Natural Immunity; Nitric Oxide; Oxidative Stress; Oxidative Stress Induction; Pathologic Processes; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Play; Process; Production; Property; Reproducibility; Research Design; Risk; Risk Factors; Role; Smooth Muscle Myocytes; Soft Tissue Disorder; Stress; System; T-Lymphocyte; Testing; Thick; Time; Tissues; Vascular Diseases; Viral; Virulent; Work; adaptive immunity; blood pressure elevation; disability; early onset; gene product; hypertensive; immunological status; innovation; mortality; mouse model; multi-scale modeling; novel; novel strategies; pharmacologic; pressure; prevent; repaired; response; sex; shear stress; soft tissue

PROJECT SUMMARY - MODELING MULTISCALE IMMUNO-MECHANICS IN AORTIC DISEASE Most vascular diseases result from, or lead to, diminished biomechanical function. Consistent with homeostatic processes tending to oppose detrimental changes in soft tissues, many vascular diseases can be attributed to compromised or lost homeostasis. Whereas mechanical homeostasis is well appreciated in large arteries, it has recently been recognized that inflammation can contribute to tissue homeostasis, though also to disease initiation and progression. There is, therefore, a need to understand together the mechano-biological and immuno- biological control of arterial geometry, composition, properties, and function. The overall goal of this project is to develop and test general data-informed computational models of immuno-mechanics from molecule to matrix. Given that hypertension is a significant risk factor for diverse vascular diseases, we will illustrate the utility of our computational model by focusing on mouse models of hypertensive aortic remodeling while examining effects of sex within the context of immune status and age of onset of the hypertension relative to different stages of aortic development. Early onset hypertension in children and adolescents is reaching epidemic proportions in the USA, but is poorly understood. We will thus gather extensive data sets that will inform and validate our novel multiscale computational models while revealing critical new understanding of aortic development and hypertensive risk. Given the complementary roles of mechanical and inflammatory homeostasis, a key goal of pharmacotherapy should be to support tissue homeostasis while limiting or preventing pathological processes. Thus, we will also collect data to contrast the efficacy of reducing either the mechanical stress (anti-hypertensive) or the oxidative stress (anti-inflammatory), or both. We hypothesize that the efficacy of a type of drug, or combination thereof, will depend on the time of onset of hypertension, particularly given that very early onset hypertension can alter aortic development by establishing new homeostatic states and set-points. To our knowledge this important understanding has not yet been addressed within a rigorous experimental-theoretical framework. This work will be founded on prior advances by our group – including consistent biomechanical phenotyping that ensures reproducibility and fundamental new concepts such as mechanobiological stability that ensure mathematical and biomechanical rigor – but will significantly extend these concepts to build a unique systems understanding of immuno-mechanics. This work is significant because of the pressing need to understand better many soft tissue diseases, particularly hypertension and its alarming increased affliction of children and adolescents (as noted by the CDC and many others); it is innovative in its approach (modeling immuno-mechanics, delineating innate and adaptive immunity) and focus (hypertensive remodeling as a function of age of onset, immune status, and sex).

项目总结-建立主动脉疾病的多尺度免疫力学模型 大多数血管疾病是由生物力学功能减退引起或导致的。与体内平衡相一致 倾向于反对软组织中的有害变化的过程，许多血管疾病可以归因于 动态平衡受损或丧失的。尽管机械动态平衡在大动脉中得到了很好的评价，但它 最近人们认识到，炎症可以促进组织内环境的稳定，尽管也会导致疾病的发生 和进步。因此，有必要一起理解机械-生物学和免疫学- 对动脉几何形状、成分、特性和功能的生物控制。这个项目的总体目标是 开发和测试从分子到基质的免疫力学通用数据通知计算模型。 鉴于高血压是各种血管疾病的重要危险因素，我们将说明我们的 通过重点研究高血压大鼠主动脉重塑模型的计算模型，同时考察丹参的作用 不同阶段的高血压患者的免疫状态和发病年龄与性别的关系 发展。在美国，早发性高血压在儿童和青少年中的流行程度正在上升， 但人们对此知之甚少。因此，我们将收集大量的数据集，这些数据集将提供信息并验证我们的新的多尺度 计算模型，同时揭示了对主动脉发育和高血压风险的关键新理解。 鉴于机械动态平衡和炎症动态平衡的互补作用，药物治疗的一个关键目标 应该是在限制或防止病理过程的同时支持组织的动态平衡。因此，我们还将 收集数据以对比降低机械应力(抗高血压)或氧化应激的效果 压力(抗炎)，或两者兼而有之。我们假设一种药物或其组合的疗效， 将取决于高血压的发病时间，特别是考虑到极早发病的高血压可以改变 通过建立新的动态平衡状态和设定点来发育主动脉。据我们所知，这很重要 理解还没有在严格的实验-理论框架内得到解决。这项工作将 建立在我们团队之前的进步基础上-包括一致的生物力学表型分析，以确保 可重复性和基本的新概念，如机械生物稳定性，确保数学和 生物力学严格性-但将显著扩展这些概念，以建立一个独特的系统理解 免疫力学。这项工作意义重大，因为迫切需要更好地了解许多软组织 疾病，特别是高血压及其令人震惊的增加了儿童和青少年的痛苦(如所指出的 疾控中心和许多其他机构)；它在方法上是创新的(对免疫机制进行建模，描绘先天和 获得性免疫)和焦点(高血压重塑作为发病年龄、免疫状态和性别的函数)。