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基本的物理、化学和生物过程的数学描述，并利用文献和我们自己的实验中的实验数据来建模的。这项工作的多尺度方面包括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，来近似细胞(和亚细胞)对血流和O2运输的影响。**最近，基于体外实验数据，我开发了红细胞内控制依赖于O2的ATP释放的第一个信号通路模型，该分子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，红细胞释放更多的三磷酸腺苷，导致扩张信号沿着内皮被上游传导到供血的小动脉。这种扩张增加了血流量，因此局部氧气供应到其红细胞饱和度降低的微血管(S)。这种将局部氧气供应与细胞需求相匹配的机制被认为在基线条件下以及当氧气消耗增加时(例如在运动中)是至关重要的。**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氧气运输相耦合，构建第一个动态(~0.1-10s)多尺度血流调节模型。在新的活体实验的支持下，将要开发的模型包括：小动脉网络中随时间变化的血流，由于ATP与内皮P2Y受体结合而引发的局部和传导内径变化，以及考虑红细胞穿越MV网络的ATP运输的新的欧拉/拉格朗日描述。**我们基于O2的动态调节模型将允许对微血管系统中的血液流动控制进行前所未有的了解，从而对微循环生理学产生重大影响。我们的欧拉/拉格朗日方法将特别适用于药物输送方法的开发，而我们的整体调控模型将有助于研究工程或治疗(促进或抗血管生成)MV网络。此外，该项目将通过对几名研究生和本科生进行微循环生理学、计算建模和活体实验方面的培训，为培养高素质的人才做出巨大贡献。

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.