Modeling Multiscale Immuno-Mechanics in Aortic Disease

点击翻译按钮获取中文摘要

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).