Integrative modeling of the microcirculation: multi-scale dynamics of oxygen-dependent blood flow regulation

为了输送氧气(通过毛细血管的扩散)和支持新陈代谢，需要有足够的血液流向所有组织。这是通过调节影响全身对流供氧的参数(心输出量、呼吸、基线血管张力)以及从器官到毛细血管网络的局部调节来实现的。局部调节由微循环控制，并决定流向器官和组织的总流量，以及这些结构内的流量和氧气分配。微血管系统的一个特点是结构的复杂性，这导致了空间上不均匀的血流。当氧气需求相对较高(运动)、血流量相对较低(缺血)或微血管结构(毛细血管密度)或功能(微动脉反应性)受损时，这种异质性尤为重要。此外，由于局部氧气供应与需求的调节过程不断匹配，微循环血流在时间上是不均匀的，当空间异质性增加时，这种情况会增加。基于微循环在输送氧气中的关键作用，以及微血管(MV)功能异质性的重要性，我的研究使用结合了真实空间和/或时间复杂性的计算模型来研究MV生理学。微循环的许多方面都是基于对潜在的物理、化学和生物过程的数学描述，并利用文献和我们自己在完整骨骼肌上进行的视频显微镜实验的数据来建模的。目前的提议将开发一个新的基于实验的计算模型，它结合了真实的几何和血流动力学复杂性，描述了基于氧依赖的红细胞释放ATP的微动脉直径和血流的稳态和动态调节以及其他生理机制，并使用多尺度建模来包括组织水平模型(MV网络)中的毛细血管尺度效应的细节。新的毛细血管-组织模型将包括空间分布的毛细血管传输和与较大血管的直接扩散相互作用，捕捉毛细血管流动方向性的对流传输，以及从毛细血管和小动脉/小静脉到更大规模的MV网络的信号传导，所有这些都将使对不同控制机制如何结合在一起产生观察到的骨骼肌调节效应的假设得到测试。我们的动态、多尺度模型代表了MV运输和调节的一种新的和独特的方法，并将作为生理学、生物工程(组织工程、药物输送)和医学(败血症、糖尿病)的未来工作的基本基础。此外，该项目将通过培训几名研究生和本科生在微循环生理学、计算建模和活体实验方面帮助高素质的人员获得有价值的新技能。

Sufficient blood flow to all tissues is required to deliver oxygen (via diffusion from capillaries) and support metabolism. This is accomplished through modulation of parameters affecting convective O2 supply to the entire body (cardiac output, breathing, baseline vascular tone), and via local modulation from organs down to capillary networks. Local modulation is controlled by the microcirculation and determines total flow to organs and tissues, and also flow and O2 distribution within these structures. A hallmark of the microvasculature is structural complexity, which results in spatially heterogeneous blood flow. This heterogeneity is particularly important when O2 demand is relatively high (exercise), flow is relatively low (ischemia), or microvascular structure (capillary density) or function (arteriolar reactivity) is compromised. In addition, due to regulatory processes continuously matching local O2 supply to demand, microcirculatory blood flow is heterogeneous in time, and this increases when spatial heterogeneity increases. Based on the key role of the microcirculation in delivering O2, and on the importance of heterogeneity in microvascular (MV) function, my research studies MV physiology using computational models that incorporate realistic spatial and/or temporal complexity. A number of aspects of the microcirculation have been modeled based on mathematical descriptions of the underlying physical, chemical and biological processes, and utilizing data from the literature and from our own video-microscopy experiments on intact skeletal muscle.  The current proposal will develop a novel experiment-based computational model that incorporates realistic geometric and hemodynamic complexity, describes steady-state and dynamic regulation of arteriolar diameters and blood flow based on O2-dependent release of ATP from RBCs and other physiological mechanisms, and uses multi-scale modeling to include details of capillary-scale effects in tissue-level models (MV networks). The new capillary-tissue model will include spatially distributed capillary transport and direct diffusive interactions with larger vessels, convective transport that captures the directionality of capillary flows, and conducted signaling from capillaries and small arterioles/venules to larger-scale MV networks, all of which will enable testing of hypotheses about how different control mechanisms combine to produce observed regulation effects in skeletal muscle. Our dynamic, multi-scale model represents a new and unique approach to MV transport and regulation, and will serve as a fundamental basis for future work in physiology, bioengineering (tissue engineering, drug delivery), and medicine (sepsis, diabetes). In addition, this project will contribute greatly to highly qualified personnel gaining valuable new skills by training several graduate and undergraduate students in microcirculatory physiology, computational modeling, and in vivo experimentation.