Microvascular O2 Delivery: Impact of Erythrocyte-Released ATP

微血管 O2 输送：红细胞释放 ATP 的影响

• 批准号: 7292312
• 负责人: MARY L ELLSWORTH
• 金额: $ 52.49万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-03 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7292312
• 关键词: Acids; Adenosine; Adenosine Triphosphate; Agreement; Algorithms; American; Animals; Arachidonic Acids; Attention; Biological; Biophysics; Blood Pressure; Blood capillaries; Blood flow; Bolus Infusion; Caliber; Cells; Collaborations; Commit; Communication; Communities; Computer Simulation; Computers; Condition; Copyright; Critiques; Data; Defect; Development; Diabetes Mellitus; Diffusion; Disease; Doctor of Medicine; Doctor of Philosophy; Dose; Endothelium; Environment; Erythrocytes; Experimental Diabetes Mellitus; Exposure to; Face; Frequencies; Functional disorder; GTP-Binding Proteins; Gases; Goals; Grant; Health; Human; Human Resources; In Vitro; Individual; Institution; Intellectual Property; International; Internet; Investigation; Knowledge; Laws; Lead; Learning; Left; Literature; Measurement; Measures; Mediating; Mediator of activation protein; Medical; Membrane; Metabolic; Metabolism; Microcirculation; Microcirculatory Bed; Microscope; Modeling; Names; Nature; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Occupations; Ontario; Oxygen; Oxygen Consumption; Pathway interactions; Physiological; Physiological Processes; Physiology; Play; Population; Preparation; Process; Production; Property; Publications; Publishing; Range; Rate; Rattus; Regulation; Research; Research Personnel; Resources; Response to stimulus physiology; Risk; Role; Saints; Science; Scientist; Severities; Signal Pathway; Signal Transduction; Signal Transduction Alteration; Simulate; Site; Skeletal Muscle; Solid; Source; Staging; Stimulus; Students; Support of Research; Surface; System; Systems Biology; Techniques; Testing; Time; TimeLine; Tissues; United States; Universities; Validation; Vascular Diseases; Vasodilation; Vasodilator Agents; Video Microscopy; Work; arteriole; autocrine; base; capillary; concept; day; diabetic; diabetic rat; experience; falls; glycemic control; help-seeking behavior; hemodynamics; human data; in vivo; insight; interest; lissamine rhodamine B; mathematical model; member; model development; network models; non-diabetic; novel; oxygen transport; paracrine; pressure; prevent; relating to nervous system; research study; response; shear stress; skills; success; symposium; theories; tissue oxygenation; tool; tripolyphosphate; vascular bed; venule

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(申请人提供)：在骨骼肌中调节氧(O2)供应以满足需求是一个如此基本的生理过程，以至于人们通常认为其机制是很好地理解的。然而，尽管已经提出了许多理论，但没有一个在体内得到充分的验证。考虑到对O2作出反应的微血管调节系统的复杂性以及O2运输的复杂性，这并不令人惊讶，在这些系统中，O2的供应由流量分布、所有血管之间的扩散O2交换以及在分支网络中流动的红细胞(RBC)的流变性决定。要解开这个生物系统的复杂性，需要一种系统生物学的方法，在这种方法中，实验提供关于我们可以确定的东西的信息，使用这些实验证据的数学计算使我们能够预测那些我们无法预测的因素。尽管氧气输送的模型自8月Krogh时代以来就存在了，但很少有人纳入必要的监管成分，因为它的身份仍然难以捉摸。最近的研究支持了携带红细胞的O2作为一个重要的调节成分的作用，通过释放三磷酸腺苷(ATP)来改变O2的供应以满足需求。在微循环中，红细胞因毛细血管或小静脉内O2张力降低而释放的ATP可通过旁分泌方式发挥作用，产生局部血管扩张以及对上游小动脉的血管扩张。红细胞来源的三磷酸腺苷也可以自分泌的方式刺激血管扩张剂环氧二十碳三烯酸(EET)从红细胞释放。这个项目的目标是证实越来越多的证据表明，红细胞在调节骨骼肌供氧与需求匹配方面发挥着关键作用。这将使用一种新的动态计算氧气传输模型，该模型基于实验数据，将微血管系统和周围组织的几何复杂性与微血管流动的网络模型以及3D组织体积内的对流和扩散氧气传输模型相结合。这一提议将确定是否依赖于氧饱和的红细胞释放的ATP对骨骼肌内氧供应的局部调节起作用。氧气调节模型将从现有的基于实验的模型开始，分阶段进行开发、测试和改进，并开发一种经验算法，模拟实验中观察到的红细胞血流动力学和氧气饱和度响应。同时，将收集暴露于低氧环境中的红细胞释放ATP和EETs以及它们在大鼠微循环中的血管活性的定量和时间数据，并用于改进模型，最终取代经验算法。糖尿病动物红细胞释放ATP的缺陷将被用来挑战调控模型。在计算模型中，用来自糖尿病大鼠模型的实验数据替代其匹配对照中获得的数据，将提供重要的新信息，说明红细胞衍生的ATP在糖尿病相关骨骼肌微循环缺陷中的重要性。调节骨骼肌供氧以匹配需氧量是一个基本的生理过程，但由于其复杂性，对其进行描述的尝试通常是不够的。越来越明显的是，因为这样的过程不能仅仅通过将它们简化为它们的组成部分来理解，所以必须使用系统生物学方法和计算建模将它们作为完整的、起作用的系统来研究。在这项建议中，我们使用系统生物学的方法来确定响应代谢需求的红细胞中的ATP释放是否负责骨骼肌内氧气供应的局部调节，并通过使用调节系统中存在缺陷的系统(2型糖尿病)来检验模型的预测，即2型糖尿病患者的红细胞中的ATP释放受到损害。