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).

项目摘要 - 在主动脉疾病中对多阶段免疫力学进行建模 大多数血管疾病是由生物力学功能降低或导致降低的。与体内平衡一致 倾向于反对软组织有害变化的过程，许多血管疾病可以归因于 妥协或失去稳态。机械稳态在大动脉中得到了很好的赞赏，但它具有 最近认识到炎症会导致组织稳态，但也有助于疾病的开始 和进展。因此，需要共同理解机械生物学和免疫 - 动脉几何形状，组成，特性和功能的生物控制。该项目的总体目标是 从分子到矩阵开发和测试免疫力学的一般数据信息的计算模型。 鉴于高血压是潜水员血管疾病的重要危险因素，我们将说明我们的实用性 计算模型通过关注高血压主动脉重塑的小鼠模型，同时检查 在主动脉的不同阶段，在免疫状态和高血压发作年龄的背景下发生性别 发展。儿童和青少年的早期高血压在美国达到流行病， 但是知之甚少。因此，我们将收集广泛的数据集，以告知和验证我们的新型多尺度 计算模型同时揭示了对主动脉发育和高血压风险的关键理解。 鉴于机械和炎症稳态的完整作用，药物治疗的关键目标 应该是在限制或预防病理过程的同时支持组织稳态。那我们也会 收集数据以对比降低机械应力（抗高血压）或氧化的效率 压力（抗炎）或两者兼而有之。我们假设某种药物的效率或组合的效率 将取决于高血压发作的时间，特别是考虑到很早的发作高血压会改变 通过建立新的稳态状态和设定点来开发主动脉开发。据我们所知，这很重要 在严格的实验理论框架内尚未解决理解。这项工作将 可以建立在我们小组的先前进步上 - 包括一致的生物力学表型，以确保 可重复性和基本新概念，例如机械稳定性，可确保数学和 生物力学严谨 - 但会大大扩展这些概念，以建立对 免疫力学。这项工作很重要，因为紧迫地需要更好地理解许多软组织 疾病，尤其是高血压及其对儿童和青少年的情感越来越令人震惊（如 疾病预防控制中心和其他许多人）；它的方法是创新的（对免疫力学建模，划定先天性和 适应性免疫学）和重点（高血压重塑作为发作年龄，免疫状态和性别的函数）。