Microvascular O2 Delivery: Impact of Erythrocyte-Released ATP

微血管 O2 输送：红细胞释放 ATP 的影响

基本信息

批准号：
7647965
负责人：
MARY L ELLSWORTH
金额：
$ 56.63万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-03 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7647965
关键词：
Acids Adenosine Adenosine Triphosphate Agreement Algorithms Animals Blood Pressure Blood capillaries Blood flow Cells Collaborations Computer Simulation Computers Data Defect Development Diabetes Mellitus Diffusion Disease Environment Erythrocytes Functional disorder Gases Goals Human In Vitro Individual Measurement Mediator of activation protein Membrane Metabolic Metabolism Microcirculation Microcirculatory Bed Microscope Modeling Nature Non-Insulin-Dependent Diabetes Mellitus Oxygen Oxygen Consumption Pathway interactions Physiological Physiological Processes Physiology Process Property Rattus Regulation Research Role Signal Pathway Signal Transduction Simulate Skeletal Muscle Staging Stimulus Surface System Systems Biology Techniques Testing Time Tissues Validation Vasodilation Vasodilator Agents Video Microscopy Work arteriole autocrine base biological systems capillary diabetic diabetic rat hemodynamics in vivo insight meetings model development network models novel oxygen transport paracrine relating to nervous system research study response shear stress skills theories tissue oxygenation tripolyphosphate vascular bed venule

项目摘要

DESCRIPTION (provided by applicant): The regulation of oxygen (O2) supply to match demand in skeletal muscle is such a fundamental, physiological process that it is often assumed that the mechanisms responsible are well understood. However, although numerous theories have been proposed, none has been adequately tested in vivo. This is not surprising given the complexity of the microvascular regulatory systems that respond to O2 as well as the complexity of O2 transport where O2 supply is determined by flow distribution, diffusional O2 exchange among all vessels and rheological properties of erythrocytes (RBCs) flowing in bifurcating networks. Unraveling the complexity of this biological system requires a systems biology approach in which experiments provide information on the things we can determine and mathematical computation using that experimental evidence enables us to predict those factors which elude us. Although models of O2 delivery have existed since the time of August Krogh, few have incorporated the necessary regulatory component since its identity has remained elusive. Recent studies have supported a role for the O2 carrying RBC as an important regulatory component that alters O2 supply to meet demand via the release of adenosine 5'-triphosphate (ATP). In the microcirculation, ATP released from RBCs in response to reduced O2 tension in capillaries or venules can function in a paracrine fashion to produce vasodilation locally as well as vasodilation that is conducted to upstream arterioles. RBC-derived ATP can also function in an autocrine fashion to stimulate the release of vasodilator epoxyeicosatrienoic acids (EETs) from RBCs. The goal of this project is to substantiate the growing evidence for a critical role for RBCs in the regulation of the matching of O2 supply with need in skeletal muscle. This will be accomplished using a new dynamic computational O2 transport model which is based on experimental data integrating the geometrical complexity of the microvasculature and surrounding tissue with a network model of microvascular flow as well as a convective and diffusive O2 transport model within a 3D tissue volume. This proposal will determine whether O2-saturation dependent release of ATP from RBCs is responsible for the local regulation of O2 supply within skeletal muscle. The O2 regulatory model will be developed, tested and refined in stages beginning with the existing experiment-based model and development of an empirical algorithm which simulates the RBC hemodynamic and O2 saturation response observed in experiments. Concomitantly, quantitative and temporal data on the release of ATP and EETs from RBCs exposed to reduced O2 and their vasoactivity in the rat microcirculation will be collected and used to refine the model, ultimately replacing the empirical algorithm. A defect in ATP release from RBCs of diabetic animals will be used to challenge the regulatory model. Substituting experimental data from a rat model of diabetes for data obtained in their matched controls in the computational model will provide important new information on the importance of RBC-derived ATP in the defect in skeletal muscle microcirculation associated with diabetes. The regulation of oxygen supply to match oxygen demand in skeletal muscle is a fundamental physiological process, yet because of its complexity, attempts to describe it have been generally inadequate. It has become increasingly obvious that because processes like these cannot be understood merely by reducing them to their component parts, they must be studied as intact, functioning systems using a systems biology approach with computational modeling. In this proposal we use a systems biology approach to determine whether the release of ATP from red blood cells in response to metabolic need is responsible for local regulation of oxygen supply within skeletal muscle and test the predictions of the model by examining it using a system (type 2 diabetes) in which there is a defect in that regulatory system, i.e., ATP release from RBCs of type 2 diabetics is compromised.

描述（由申请人提供）：氧气（O2）供应以符合骨骼肌需求的调节是一个基本的生理过程，通常可以假定对所造成的机制有充分的理解。但是，尽管已经提出了许多理论，但在体内没有经过充分的测试。鉴于对O2响应的微血管调节系统的复杂性以及O2转运的复杂性，其中O2供应取决于流动分布，所有血管之间的扩散O2交换以及在生育网络中流动的所有血管（RBC）的复杂性。阐明该生物系统的复杂性需要一种系统生物学方法，在该方法中，实验提供了有关我们可以确定的事物的信息和使用该实验证据的数学计算的信息，使我们能够预测那些避免我们的因素。尽管自奥古斯特·克罗格（August Krogh）以来，已经存在O2交付模型，但由于其身份仍然难以捉摸，很少有人纳入了必要的监管组件。最近的研究支持了携带RBC的O2作为重要的调节成分的作用，该组件通过释放5'-三磷酸腺苷（ATP）来改变O2供应以满足需求。在微循环中，响应于毛细血管或静脉的O2张力而释放的ATP可以以旁分泌方式起作用，以在局部产生血管舒张，以及用于上游动脉的血管舒张。 RBC衍生的ATP还可以以自分泌方式发挥作用，以刺激RBC的血管舒张释放释放的环氧酸环卫星酸（EET）。该项目的目的是证实越来越多的证据证明了RBC在调节O2供应与骨骼肌需求的调节中发挥关键作用。这将使用新的动态计算O2传输模型来实现，该模型基于实验数据，该模型将微血管及周围组织的几何复杂性与微血管流动的网络以及3D组织体积内的对流和扩散的O2传输模型相结合。该提案将确定ATP从RBCS中释放的O2饱和释放是否负责骨骼肌内O2供应的局部调节。 O2调节模型将以基于实验的模型和经验算法的开发开发，测试和完善，并在实验中观察到的RBC血液动力学和O2饱和反应。同时，将收集暴露于O2降低的RBC的ATP和EET的定量和时间数据，将收集大鼠微循环中的血管活性，并用于完善模型，最终取代经验算法。从糖尿病动物的RBC中释放ATP的缺陷将用于挑战调节模型。从糖尿病大鼠模型中替换实验数据，以在计算模型中获得的数据中获得的数据将提供有关RBC衍生的ATP在与糖尿病相关的骨骼肌微循环缺陷中的重要性的重要新信息。氧气供应对骨骼肌的氧气需求匹配是一个基本的生理过程，但是由于其复杂性，试图描述其通常是不足的。越来越明显的是，由于不能仅通过将它们减少到其组件部分来理解之类的过程，因此必须使用系统生物学方法和计算建模的系统生物学方法将它们作为完整的功能系统进行研究。 In this proposal we use a systems biology approach to determine whether the release of ATP from red blood cells in response to metabolic need is responsible for local regulation of oxygen supply within skeletal muscle and test the predictions of the model by examining it using a system (type 2 diabetes) in which there is a defect in that regulatory system, i.e., ATP release from RBCs of type 2 diabetics is compromised.

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pre-diabetes augments neuropeptide Y1- and α1-receptor control of basal hindlimb vascular tone in young ZDF rats.

糖尿病前期增强了神经肽 Y1- 和 α1- 受体对年轻 ZDF 大鼠基础后肢血管张力的控制。

DOI：
10.1371/journal.pone.0046659
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Novielli,NicoleM;Al-Khazraji,BaraaK;Medeiros,PhilipJ;Goldman,Daniel;Jackson,DwayneN
通讯作者：
Jackson,DwayneN

Vascular disease in pre-diabetes: new insights derived from systems biology.