Flow regulation and oxygen transport in microcirculation

描述（申请人提供）：血流调节是心血管生物学的中心课题。许多疾病涉及功能失调的血流调节，血管活性药物经常用于治疗这些疾病。提供充足的氧气供应是循环系统最关键的功能。该项目的总体目标是建立微血管网络中血流调节和氧运输的定量理论模型。在该基金支持的先前研究中，我们开发了一个具有均匀结构的网络中的稳态流量调节模型。该模型将成为拟议研究的基础，为红细胞在血流调节中肌生成、代谢、剪切依赖和传导反应以及氧依赖释放ATP的作用提供了见解。在本文中，我们将研究非均质性、随时间变化的行为和毛细血管招募对流动调节的影响。具体目标1是建立具有非均匀结构和空间变化代谢需求的微血管网络流量调节的理论模型。这些模型将用于研究灌注在正常组织中与代谢需求局部匹配的机制，以及这种机制在异常状态下是如何失效的。具体目标2是建立响应代谢需求和动脉压力变化的时间依赖性血流调节的理论模型，并应用该模型分析在某些情况下发生的小动脉直径和血流的自发振荡（小动脉血管舒缩）。具体目标3是建立包括毛细血管募集影响的理论模型，并测试其描述超过25倍观察到的骨骼肌灌注动态范围的能力。在所有这些研究中，重点将放在将模型预测与现有实验数据进行比较，并使用这些数据进一步开发、测试和完善模型。Axel Pries博士和Tuhin Roy博士这两位顾问分别在相关的实验基础科学和临床领域拥有丰富的经验，他们建立了良好的合作关系，将促进这一进程。

DESCRIPTION (provided by applicant): Regulation of blood flow is a central topic in cardiovascular biology. Many disorders involve dysfunctional flow regulation, and vasoactive drugs are frequently used in treating these disorders. Delivery of an adequate oxygen supply is the most critical function of the circulatory system. The overall objective of this project is to develop quantitative theoretical models for blood flow regulation and oxygen transport in microvascular networks. In prior studies supported by this grant, we developed a model for steady-state flow regulation in a network with a homogeneous structure. That model, which will form the basis for the proposed studies, has provided insights into the roles of myogenic, metabolic, shear-dependent and conducted responses and oxygen-dependent release of ATP by red blood cells in the regulation of flow. In the proposed work, we will examine the effects of heterogeneity, time-dependent behavior and capillary recruitment on flow regulation. Specific Aim 1 is to develop theoretical models for flow regulation in microvascular networks with inhomogeneous structures and spatially varying metabolic demand. The models will be used to investigate the mechanisms by which perfusion is locally matched to metabolic demand in normal tissue and how this fails in abnormal states. Specific Aim 2 is to develop theoretical models for time- dependent flow regulation in response to changes in metabolic demand and arterial pressure, and to apply this model to analyze spontaneous oscillations in arteriolar diameter and blood flow (arteriolar vasomotion) that occur in some conditions. Specific Aim 3 is to develop theoretical models including effects of capillary recruitment, and to test their ability to describe the more than 25-fold observed dynamic range of skeletal muscle perfusion. In all these studies, emphasis will be placed on comparing model predictions with available experimental data and using these data to further develop, test and refine the models. This process will be facilitated by well established collaborations with two consultants, Dr. Axel Pries and Dr. Tuhin Roy, who have extensive experience in relevant experimental basic science and clinical areas respectively. PUBLIC HEALTH RELEVANCE: How blood flow is regulated, i.e., how perfusion is matched to tissue demands and maintained despite changes in arterial pressure, is a central question in cardiovascular biology. The overall objective of the proposed studies is to develop quantitative theoretical models for blood flow regulation and oxygen transport in microvascular networks. The models will clarify the roles of mechanisms that coordinate blood flow with local tissue requirements, will provide a rational structure for interpreting experimental data, and may lead to improved therapeutic approaches for controlling tissue perfusion.