Flow regulation and oxygen transport in microcirculation

描述（由申请人提供）：血流调节是心血管生物学的中心主题。许多疾病涉及血流调节功能障碍，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。在先前的研究中，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，它提供了对肌源性、代谢性、剪切依赖性和传导性反应以及红细胞在流量调节中ATP的氧依赖性释放的作用的见解。在拟议的工作中，我们将研究的异质性，时间依赖性行为和毛细血管募集对流量调节的影响。具体目标1是发展的理论模型，在微血管网络的流量调节与非均匀结构和空间变化的代谢需求。这些模型将用于研究灌注与正常组织中的代谢需求局部匹配的机制，以及在异常状态下如何失败。具体目标2是开发响应代谢需求和动脉压变化的时间依赖性流量调节的理论模型，并应用该模型分析在某些条件下发生的小动脉直径和血流的自发振荡（小动脉血管运动）。具体目标3是开发包括毛细血管募集效应的理论模型，并测试其描述超过25倍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的实验数据进行比较，并利用这些数据进一步开发，测试和完善模型。这一过程将通过与两名顾问阿克塞尔普里斯博士和图欣罗伊博士的良好合作来促进，他们分别在相关的实验基础科学和临床领域拥有丰富的经验。 公共卫生相关性：如何调节血流，即，灌注如何与组织需求相匹配并在尽管动脉压变化的情况下保持灌注是心血管生物学中的中心问题。提出的研究的总体目标是发展定量的理论模型，血流调节和微血管网络中的氧气运输。这些模型将阐明协调血流与局部组织要求的机制的作用，将提供一个合理的结构来解释实验数据，并可能导致控制组织灌注的改进治疗方法。

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.