Modeling Multiscale Immuno-Mechanics in Aortic Disease

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的。符合体内平衡 倾向于对抗软组织中有害变化的过程，许多血管疾病可归因于 破坏或失去体内平衡。尽管机械稳态在大动脉中得到很好的评价， 最近认识到，炎症可有助于组织稳态，尽管也可导致疾病的发生 和进步。因此，有必要共同理解机械生物学和免疫学。 动脉几何形状、组成、性质和功能的生物控制。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 通过关注高血压主动脉重构的小鼠模型，同时检查 免疫状态下的性别和相对于主动脉不同阶段的高血压发病年龄 发展在美国，儿童和青少年早发性高血压已达到流行病的比例， 但人们对此知之甚少。因此，我们将收集广泛的数据集，这些数据集将为我们新颖的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，药物治疗的一个关键目标是 应该是支持组织稳态，同时限制或防止病理过程。因此，我们也将 收集数据以对比降低机械应力（抗高血压）或氧化应激（抗高血压）的功效。 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， 将取决于高血压发作的时间，特别是考虑到非常早期发作的高血压可以改变 通过建立新的稳态和设定点来促进主动脉发育。据我们所知， 理解尚未在严格的实验-理论框架内得到解决。这项工作将 建立在我们小组先前的进展基础上-包括一致的生物力学表型， 再现性和基本的新概念，如机械生物学稳定性，确保数学和 生物力学严谨性-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 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，特别是高血压及其对儿童和青少年的折磨令人震惊地增加（如《世界卫生组织报告》所指出的那样）。 疾病预防控制中心和许多其他机构）;它在方法上是创新的（模拟免疫机制，描绘先天和 适应性免疫）和病灶（作为发病年龄、免疫状态和性别的函数的高血压重塑）。

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).