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

所有组织都需要足够的血流来输送氧气（通过毛细血管的扩散）和支持新陈代谢。这是通过调节影响全身对流O2供应的参数（心输出量、呼吸、基线血管张力）以及通过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，并决定器官和组织的总流量，以及这些结构内的流量和O2分布。微脉管系统的一个特点是结构复杂性，这导致空间上不均匀的血流。当O2需求相对较高（运动）、流量相对较低（缺血）或微血管结构（毛细血管密度）或功能（小动脉反应性）受损时，这种异质性尤其重要。此外，由于调节过程不断匹配局部O2供应与需求，微循环血流在时间上是异质的，并且当空间异质性增加时，这种异质性增加。基于微循环在提供O2中的关键作用，以及微血管（MV）功能异质性的重要性，我的研究使用结合现实空间和/或时间复杂性的计算模型来研究MV生理学。微循环的许多方面已经基于对基本物理、化学和生物过程的数学描述，并利用来自文献和我们自己的实验的实验数据来建模。这项工作的多尺度方面涉及近似的细胞（和亚细胞）对血流和O2运输的影响，基于这些尺度的建模，并在更大尺度的模型（MV网络）中使用这些近似。最近，基于体外实验数据，我开发了红细胞内信号通路的第一个模型，该信号通路控制ATP的O2依赖性释放，ATP是一种被认为是控制局部血流分布的关键分子。随着红细胞中血红蛋白的氧饱和度降低，红细胞释放的ATP量增加，导致扩张信号沿内皮沿着向上游传导至供血小动脉。这种扩张增加了血流量，因此增加了局部O2供应到RBC饱和度降低的微血管。这种将局部O2供应与蜂窝需求相匹配的机制被认为在基线条件下和当O2消耗增加时（例如，在练习中）。拟议的研究将通过将细胞内ATP释放途径与整个小动脉树上的流量和O2运输耦合，构建第一个通过RBC中O2依赖性ATP释放进行血流调节的动态（~0.1- 10 s）多尺度模型。待开发的模型，支持新的体内实验，包括时间依赖性的小动脉网络中的血流，由于ATP结合到内皮P2 Y受体，和一个新的欧拉/拉格朗日描述的ATP运输，认为红细胞穿越MV网络的局部和进行的直径变化的启动。我们的动态模型的O2为基础的调节将允许前所未有的水平的理解血流控制的微血管系统，因此有一个重大的影响微循环生理学。我们的欧拉/拉格朗日方法将特别适用于药物递送方法的开发，而我们的整体调控模型将有助于研究工程或治疗性处理（促或抗血管生成）的MV网络。此外，该项目将大大有助于培养高素质的人才，通过培训几个研究生和本科生在微循环生理学，计算建模和体内实验。

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 experimental data from the literature and our own experiments. The multiscale aspect of this work involves approximation of cellular (and subcellular) effects on blood flow and O2 transport, based on modeling at these scales, and using these approximations in models at much larger scales (MV networks). Recently, based on in vitro experimental data, I developed the first model of the signaling pathway inside RBCs that controls O2-dependent release of ATP, a molecule believed key in controlling local distribution of blood flow. As the O2 saturation of hemoglobin in RBCs decreases, RBCs release increasing amounts of ATP, causing a dilation signal that is conducted upstream along the endothelium to feeding arterioles. This dilation increases blood flow and hence local O2 supply to the microvessel(s) whose RBCs experienced decreased saturation. This mechanism for matching local O2 supply to cellular demand is believed to be crucial under baseline conditions and when O2 consumption increases (e.g., in exercise). The proposed research will construct the first dynamic (~0.1-10s) multiscale model of blood flow regulation via O2-dependent release of ATP from RBCs, by coupling the intracellular ATP release pathway to flow and O2 transport over the entire arteriolar tree. Models to be developed, supported by novel in vivo experiments, include time-dependent blood flow in arteriolar networks, initiation of local and conducted diameter changes due to ATP binding to endothelial P2Y receptors, and a novel Eulerian/Lagrangian description of ATP transport that considers RBCs traversing MV networks. Our dynamic model of O2-based regulation will permit an unprecedented level of understanding of blood flow control in the microvasculature, and therefore have a major impact on microcirculatory physiology. Our Eulerian/Lagrangian approach will be particularly applicable to development of drug delivery methods, while our overall regulation model will be useful in studying engineered or therapeutically-treated (pro- or anti-angiogenic) MV networks. In addition, this project will contribute greatly to the training of highly qualified personnel by training several graduate and undergraduate students in microcirculatory physiology, computational modeling, and in vivo experimentation.