Multiscale modeling of cerebral blood flow and oxygen transport

脑血流和氧运输的多尺度建模

基本信息

批准号：
10231113
负责人：
Timothy W. Secomb
金额：
$ 39.79万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231113
关键词：
Address Affect Alzheimer&apos s Disease Arizona Arteries Behavior Biological Process Blood Blood Vessels Blood capillaries Blood flow Brain Brain Injuries Brain imaging Caliber Cardiovascular system Cerebral cortex Cerebrovascular Circulation Cerebrum Chronic Computer Models Data Development Disease Erythrocytes Functional Magnetic Resonance Imaging Generations Goals Homeostasis Hypertension Hypotension Hypoxia Image Impairment Individual Lead Link Literature Maps Measures Mechanics Metabolic Methods Microcirculation Microscopic Modeling Multimodal Imaging Mus Neurodegenerative Disorders Normal Range Optical Coherence Tomography Oxygen Oxyhemoglobin Pathologic Perfusion Physiological Physiology Property Regulation Reporting Resistance Resolution Role Stimulus Striated Muscles Stroke Structure Testing Theoretical model Tissues Universities Validation Vascular System Vascular blood supply Work arteriole base blood perfusion brain tissue experimental group experimental study hemodynamics improved in vivo insight medical schools microscopic imaging model development multi-scale modeling nanoprobe neurovascular neurovascular coupling next generation oxygen transport parallel computer phosphorescence physical process predictive modeling relating to nervous system response simulation three dimensional structure tissue oxygenation two photon microscopy

项目摘要

The overall goal of this proposal is to gain quantitative understanding of the relationship between neural activation, blood flow and tissue oxygenation in the brain cortex, using multiscale theoretical models for blood flow, oxygen transport and flow regulation in networks of microvessels. Adequate blood flow to meet spatially and temporally varying demands of brain tissue is crucial, since lack of oxygen quickly leads to irreversible damage. The mechanisms by which blood flow is controlled are poorly understood. Multiple interactions between neural activity, metabolite levels, changes in vascular tone, network blood flow, and oxygen transport are difficult to unravel, and cannot be understood just by observing behavior of individual blood vessels. In the proposed work, the detailed structure of microvessel networks with thousands of segments in the mouse cerebral cortex will be imaged using two-photon microscopy. Observations using phosphorescence quenching nanoprobes will yield high resolution maps of tissue oxygen levels. Spectral domain optical coherence tomography will be used to measure blood flows. The multiscale modeling approach simulates biological and physical processes at the capillary diameter and cellular scale (~10 μm, including flow mechanics and active responses of vessel walls to hemodynamic, neural and metabolic stimuli), at the vessel scale (~100 μm, including segment flow resistance, oxygen loss and propagation of conducted responses along vessel walls) and at the network and tissue scale (~1000 μm, including entire network flows, perfusion, oxygen extraction and tissue hypoxic fraction). Specific Aim 1 is to develop predictive multiscale models for blood flow and oxygen transport in the mouse cerebral cortex, and validate these models using experimental data derived from multimodal imaging of the cortex microvasculature. The proposed studies will provide a model that will reconcile available data at the microscopic level with macroscopic level variables such as perfusion and oxygen extraction and will allow prediction of tissue oxygenation and occurrence of hypoxia for a range of blood perfusion and oxygen demand. Specific Aim 2 is to develop multiscale models for blood flow autoregulation and neurovascular coupling in the mouse cerebral cortex, and to test and refine these models using experimental data derived from multimodal imaging of the cortical microvasculature. The models will include effects of myogenic, metabolic, shear-dependent and conducted responses, as well as the possible role of capillary-level regulation. Models including or excluding these mechanisms will be tested for their ability to represent actual regulatory responses, as reported in the literature and as observed in multimodal imaging experiments under varying physiological conditions. Improved understanding of the mechanisms of flow regulation could lead to improved strategies for disorders related to neurovascular function, including stroke and neurodegenerative diseases, and for interpreting fMRI brain imaging.

该提案的总体目标是对使用多尺度理论，脑皮质中的神经激活，血流和组织氧合微血管网络中的血流，氧运输和流动调节模型。足够的血液流以空间和暂时变化的脑组织需求是至关重要的，因为缺乏氧气迅速导致不可逆转的损害。控制血流的机制知之甚少。神经活动，代谢物水平，血管张力变化，网络血流的变化之间的多种相互作用，和氧运输很难解散，不能仅通过观察个体的行为来理解血管。在拟议的工作中，具有数千个微血管网络的详细结构小鼠大脑皮层中的片段将使用两光子显微镜成像。观察结果磷光猝灭纳米探针将产生组织氧水平的高分辨率图。光谱域光学相干断层扫描将用于测量血流。多尺度建模方法在毛细管直径和细胞尺度上模拟生物学和物理过程（〜10μM，包括流量血管壁对血液动力学，神经和代谢刺激的力学和主动反应，在血管处比例尺（〜100μm，包括段流阻力，氧损失和传播的反应沿着容器壁）和网络和组织尺度（〜1000μm，包括整个网络流，灌注，氧气提取和组织缺氧部分）。特定目标1是开发预测性多尺度模型用于小鼠大脑皮层中的血流和氧转运，并使用这些模型验证这些模型从皮质微脉管系统的多模式成像得出的实验数据。提议研究将提供一个模型，该模型将在微观级别调和可用数据与宏观水平诸如灌注和氧气提取等变量，将允许组织氧合和目标2是发展小鼠脑中血流自动调节和神经血管耦合的多尺度模型皮质，并使用源自多模式成像的实验数据来测试和完善这些模型皮质微举行。这些模型将包括肌原性，代谢，剪切依赖性的效果并进行了反应，以及毛细管级调节的可能作用。包括OR在内的型号除了这些机制外，将测试其代表实际监管响应的能力，例如在文献中报道了在不同生理学下的多模式成像实验中观察到的状况。对流动调节机制的理解有所提高，可能会改善策略与神经血管功能有关的疾病，包括中风和神经退行性疾病，以及针对解释fMRI脑成像。