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

项目总结 痴呆症是一种衰弱综合征，有许多使人丧失能力的症状，需要依赖护理，即 对患者及其家人来说，这在情感上和经济上都是负担。痴呆症是第六大诱因 美国死亡人数为4750万，目前患有痴呆症，预计 到2030年达到7560万，到2050年达到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僵硬是一个主要的 导致痴呆症的因素，但其发生机制(S)仍不清楚。在健康的个体中， 通过脉动性抑制，大血管中的脉动流转变为脑血管中的连续流 通过大动脉。随着时间的推移，反复的扩张和松弛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，从而减少顺应性和抑制。这将导致 在脑微血管从连续血流到脉动血流的转换中，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- 诱导损伤机制中，内皮细胞和神经元对应变也很敏感。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 神经元损伤。我们将通过两个目标的实现来检验我们的假设。(1)调查独立人士，以及 循环剪应力和循环应变对BMEC的综合影响、转化和增加 功能障碍和炎症。我们假设从连续流到脉动流的转换，以及 在脉搏波速度方面，通过暴露于增加的循环切应力，导致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，以及由于 脉压升高，加重切变诱导的BMEC功能障碍。(2)研究循环荷载的影响。 神经损伤的应激反应。我们假设，随着脉压的增加，相关的应变增加将 通过应变传播到血管附近的组织和神经元诱导神经元损伤，这一过程 随着年龄相关的大脑软化而恶化。这项提案的结果将为我们提供重要的见解 动脉硬化引起的病理血流动力学导致骨髓微血管内皮细胞和神经元损伤。

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.