Quantifying the Influence of Pathological Hemodynamics on Cerebral Microvascular Dysfunction and Neuronal Injury

量化病理血流动力学对脑微血管功能障碍和神经元损伤的影响

• 批准号: 10475093
• 负责人: John Hundley Slater
• 金额: $ 32.65万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475093
• 关键词: Actins; Arteries; Blood; Blood capillaries; Brain; Brain Injuries; Bulla; Cadherins; Caliber; Caring; Cause of Death; Cell physiology; Cells; Centers of Research Excellence; Cerebrum; Cessation of life; Clinical Research; Collagen; Coupled; Dementia; E-Selectin; Elasticity; Elastin; Elements; Emotional; Endothelial Cells; Engineering; Etiology; Exposure to; Family; Focal Adhesions; Functional disorder; Heart; Hydrogels; Hypertension; Impaired cognition; Individual; Inflammation; Injury; Investigation; Lead; Link; Maps; Measurement; Measures; Mediating; Microfluidics; Microvascular Dysfunction; Modeling; Molecular; Nanosphere; Nerve Degeneration; Neurites; Neuronal Dysfunction; Neuronal Injury; Neurons; Pathologic; Patients; Periodicity; Permeability; Persons; Physiologic pulse; Play; Population; Process; Pulsatile Flow; Pulse Pressure; Reactive Oxygen Species; Relaxation; Resolution; Role; Symptoms; Synapses; Syndrome; Testing; Thinness; Time; Tissues; United States; Vascular Cell Adhesion Molecule-1; age related; aging hippocampus; arterial stiffness; arteriole; base; brain endothelial cell; cardiovascular health; cell injury; cerebral microvasculature; disability; endothelial dysfunction; ethylene glycol; hemodynamics; in vitro Model; in vivo; injured; innovation; insight; neurovascular; novel therapeutic intervention; pressure; shear stress; soft tissue

PROJECT SUMMARY Dementia is a debilitating syndrome with many incapacitating symptoms requiring dependent care that is emotionally and financially burdensome for patients and their families. Dementia is the 6th leading cause of death in the United States with 47.5 million people worldwide currently living with dementia which is projected to reach 75.6 million by 2030 and 135.5 million by 2050. Unfortunately, no therapies to treat dementia exist, indicating a critical and urgent need for a better understanding of how dementia is initiated and progresses so that new therapeutic approaches can be developed. Age-related stiffening of the large elastic arteries is a major contributor to dementia but the mechanism(s) by which this occurs remain unknown. In healthy individuals, pulsatile flow in large vessels is converted to continuous flow in cerebral µvasculature via pulsatility dampening by large arteries. Repeated cycles of distension and relaxation over time induce irreversible elastin fragmentation in large arteries which is replaced by stiffer collagen thereby diminishing compliance and dampening. This results in the conversion from continuous to pulsatile flow in cerebral microvasculature accompanied by increases in pulse pressure and pulse wave velocity. These pathological hemodynamics have been linked to cognitive decline via neuronal injury, synaptic dysfunction, and neurodegeneration. While most hypotheses focus on shear- induced injury mechanisms, endothelial cells and neurons are also sensitive to strain. We hypothesize that induction of cyclic strain, in the microvessel wall and adjacent tissue, due to the conversion to pulsatile flow, exacerbates shear-induced brain microvascular endothelial cell (BMEC) dysfunction and is the primary cause of neuronal injury. We will test our hypotheses via fulfillment of two aims. (1) Investigate the independent, and combined influences of, conversion to, and increases in, cyclic shear stress and cyclic strain on BMEC dysfunction and inflammation. We hypothesize that conversion from continuous to pulsatile flow, and an increase in pulse wave velocity, induce BMEC dysfunction and inflammation via exposure to increased cyclic shear stress. We further hypothesize that cyclic strain in the microvascular wall, and increase in strain magnitude due to increased pulse pressure, exacerbate shear-induced BMEC dysfunction. (2) Investigate the influence of cyclic strain on neuronal injury. We hypothesize that as pulse pressure increases, the associated increase in strain will induce neuronal injury via strain propagation into tissue and neurons adjacent to the vessel and that this process worsens with age-related brain softening. The results of this proposal will provide significant insight into how pathological hemodynamics induced by arterial stiffening lead to BMEC and neuronal injury.

项目概要 痴呆症是一种使人衰弱的综合征，具有许多丧失行为能力的症状，需要依赖护理 给患者及其家属带来精神和经济负担。痴呆症是第六大病因 目前全球有 4750 万人患有痴呆症，预计将导致美国死亡 到 2030 年，这一数字将达到 7560 万，到 2050 年将达到 1.355 亿。不幸的是，目前还没有治疗痴呆症的疗法， 表明迫切需要更好地了解痴呆症是如何发生和发展的 可以开发新的治疗方法。与年龄相关的大弹性动脉硬化是一个主要原因 导致痴呆，但发生这种情况的机制仍不清楚。在健康个体中， 大血管中的脉动流通过脉动抑制转化为脑微血管中的连续流 通过大动脉。随着时间的推移，反复的扩张和放松循环会导致不可逆的弹性蛋白断裂 在大动脉中，它被更硬的胶原蛋白取代，从而减少顺应性和阻尼。这个结果 脑微血管从连续血流转变为脉动血流，伴随着 脉压和脉搏波速度。这些病理性血流动力学与认知能力下降有关 通过神经元损伤、突触功能障碍和神经变性。虽然大多数假设都集中在剪切力上 在诱发损伤机制中，内皮细胞和神经元也对应变敏感。我们假设 由于转换为脉动流，在微血管壁和邻近组织中诱导循环应变， 加剧剪切诱导的脑微血管内皮细胞 (BMEC) 功能障碍，是导致 神经元损伤。我们将通过实现两个目标来检验我们的假设。 (1) 调查独立的，并且 循环剪切应力和循环应变对 BMEC 的综合影响、转换和增加 功能障碍和炎症。我们假设从连续流到脉动流的转换，并且增加 脉搏波速度，通过暴露于增加的循环剪切应力诱导 BMEC 功能障碍和炎症。 我们进一步假设微血管壁中的循环应变以及应变大小的增加是由于 脉压增加，加剧剪切引起的 BMEC 功能障碍。 (2)考察循环的影响 神经元损伤的紧张。我们假设随着脉压增加，应变也会随之增加 通过应变传播到血管附近的组织和神经元来诱导神经元损伤，并且该过程 随着年龄相关的大脑软化而恶化。该提案的结果将提供重要的见解 动脉硬化引起的病理血流动力学导致 BMEC 和神经元损伤。