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 - 主动脉疾病的多尺度免疫力学建模 大多数血管疾病是由生物力学功能减弱引起或导致的，这与体内平衡一致。 倾向于反对软组织变化的过程，许多血管疾病可归因于 在大动脉中，机械稳态受到损害或丧失。 最近人们认识到炎症可以促进组织稳态，但也可以促进疾病的发生 因此，有必要一起了解机械生物学和免疫学。 动脉几何形状、成分、特性和功能的生物控制 该项目的总体目标是 开发和测试从分子到矩阵的免疫力学的通用数据通知计算模型。 鉴于高血压是多种血管疾病的重要危险因素，我们将说明我们的实用性 通过关注高血压主动脉重塑的小鼠模型同时检查以下因素的影响来建立计算模型 免疫状态和高血压发病年龄与主动脉不同阶段的性别关系 在美国，儿童和青少年的早发性高血压已达到流行病的程度。 但我们对此知之甚少，因此我们将收集大量数据集，为我们的新颖多尺度提供信息和验证。 计算模型，同时揭示了对主动脉发育和高血压风险的重要新认识。 鉴于机械和炎症稳态的互补作用，这是药物治疗的一个关键目标 应该是支持组织稳态，同时限制或预防病理过程。因此，我们也将。 收集数据来对比减少机械应激（抗高血压）或氧化应激的功效 我们捕获了一种药物或其组合的功效， 取决于高血压的发病时间，特别是考虑到早期发病的高血压可能会改变 据我们所知，通过建立新的稳态和设定点来促进主动脉发育，这一点很重要。 这项工作尚未在严格的实验理论框架内解决这一问题。 建立在我们团队先前的进步之上——包括一致的生物力学表型，确保 再现性和基本的新概念，例如机械生物学稳定性，确保数学和 生物力学的严谨性——但将显着扩展这些概念，以建立对生物力学的独特系统理解 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，特别是高血压及其对儿童和青少年的令人担忧的增加（正如 CDC 和许多其他机构）；它的方法具有创新性（建模免疫机制、描述先天和 适应性免疫）和焦点（高血压重塑作为发病年龄、免疫状态和性别的函数）。