A mechanistic understanding of glymphatic transport and its implications in neurodegenerative disease

对类淋巴运输的机制及其在神经退行性疾病中的影响的理解

• 批准号: 10742654
• 负责人: Shaolie Samira Hossain
• 金额: $ 43.84万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742654
• 关键词: 3-Dimensional; Affect; Age Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer’s disease biomarker; American; Amyloid; Amyloid beta-Protein; Amyloid deposition; Anatomy; Architecture; Automobile Driving; Biological Markers; Blood Vessels; Brain; Brain region; Cerebrospinal Fluid; Characteristics; Clinical Trials; Cognitive; Computer Models; Coupled; Data; Deposition; Development; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Exercise; Exhibits; Female; Foundations; Future; Geometry; Goals; Hippocampus; Histology; Human; Image; Intercellular Fluid; Magnetic Resonance Imaging; Measures; Methods; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pathologic; Pathway interactions; Pattern; Physiological; Play; Pre-Clinical Model; Predisposition; Process; Property; Proteins; Research; Role; System; Testing; Therapeutic Intervention; Three-Dimensional Imaging; Time; Transgenic Mice; Transport Process; Work; abeta deposition; brain volume; cerebrospinal fluid flow; clinical translation; cohort; conditioning; contrast enhanced; experimental study; flexibility; glymphatic dysfunction; glymphatic function; glymphatic system; high resolution imaging; image guided; imaging Segmentation; improved; in vivo; insight; male; mental function; motor impairment; mouse model; neurogenesis; neuron loss; novel; novel strategies; predictive modeling; presenilin-1; prevent; preventive intervention; simulation; small molecule; tau Proteins; three-dimensional modeling; wasting; β-amyloid burden

Abstract: An estimated 6.5 million Americans suffer from neurodegenerative diseases such as Alzheimer’s Disease (AD) and Parkinson’s Disease that result in progressive degeneration and death of nerve cells (neurons) impairing movement and/or mental functioning. Delayed clearance of key biomarkers of AD, including amyloid-beta (Aβ) and tau agglomerates, has been suggested as a possible mechanism for triggering neurodegeneration that could lead to AD. To date, however, there is little to no quantitative and mechanistic understanding of the transport and clearance of small molecules, agglomerates, and debris from the brain. Such clearance is thought to occur through a brain-wide perivascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange, known as the glymphatic system. Characterization of glymphatic transport is currently limited, however, well-validated 3D computational models may enable quantification of the transport and clearance of key AD biomarkers throughout the brain. The long-term goal of this proposal is to develop an integrated toolset of image-based computational modeling to describe subject-specific glymphatic transport that is experimentally parameterized and validated. We propose a novel approach, using an immersed isogeometric method, where the transport model is constructed directly from the 3D imaging data, resulting in a flexible, subject-specific model that accounts for anatomical geometry and heterogeneous material properties. Our preliminary studies indicate that transport parameters such as CSF flow velocity play a large role in Aβ deposition. We hypothesize that 1) amyloid-bearing mice exhibit differences in glymphatic function, including CSF flow velocity, which lead to Aβ deposition and that 2) increased exercise in a mouse model of amyloid deposition will improve glymphatic function and reduce amyloid deposition. The main objective therefore is to 1) parameterize subject-specific 3D models of glymphatic transport and study brain-wide deposition of proteins under pathological conditions in amyloid bearing mice, and 2) model the effects of exercise on glymphatic transport and subsequent amyloid deposition. Our advanced image-guided modeling of glymphatic transport tightly integrated with experiments and adjusted with subject-specific attributes, offers a unique opportunity to quantitatively assess the effect of glymphatic dysfunction on waste clearance and study how specific factors such as exercise drive glymphatic function and protein deposition. The proposed research is significant because it will provide an architecturally and physiologically faithful platform, grounded in experiments, for informing future preventive and therapeutic interventions in neurodegenerative disease.

摘要：估计有650万美国人患有神经退行性疾病，例如 阿尔茨海默氏病（AD）和帕金森氏病，导致进行性变性和 神经细胞（神经元）的死亡损害运动和/或精神功能。延迟间隙 已经提出了包括淀粉样蛋白β（Aβ）和tau凝集物在内的AD关键生物标志物的 作为触发可能导致AD的神经变性的可能机制。迄今为止， 但是，对运输的数量和机械理解几乎没有 大脑的小分子，团聚和碎屑的清除。这样的清关 通过脑血管周围途径发生脑脊液（CSF）和间质发生 流体（ISF）交换，称为糖基系统。糖型传输的特征 但是，目前有限，但是，经过验证的3D计算模型可以实现定量 整个大脑中关键AD生物标志物的运输和清除。长期目标 该建议是将基于图像的计算建模的集成工具集开发为 描述受试者特异性的糖型转运，该糖型转运经过实验性参数化和验证。 我们提出了一种新颖的方法，使用浸入的同几何方法，其中传输 模型是直接从3D成像数据构建的，导致了灵活的，特定于主题的 解释解剖学几何形状和异质材料特性的模型。我们的 初步研究表明，诸如CSF流速度之类的传输参数起着很大的作用 在Aβ沉积中。我们假设1）承重淀粉样蛋白的小鼠暴露于糖糖的差异 功能，包括CSF流速度，导致Aβ沉积和2）增加运动 在淀粉样蛋白沉积的小鼠模型中，将改善糖化功能并减少淀粉样蛋白 沉积。因此，主要目标是1）参数化特定于主题的3D模型 在病理条件下，蛋白质的囊肿运输和研究蛋白质的整个大脑沉积 淀粉样蛋白轴承小鼠，2）建模运动对糖型运输的影响和 随后的淀粉样沉积。我们的高级图像指导建模 与实验紧密整合并与特定于主题的属性进行了调整，提供了独特的 定量评估糖性功能障碍对废物清除和 研究诸如锻炼之类的特定因素如何驱动甘氨酸功能和蛋白质沉积。 拟议的研究很重要，因为它将在体系结构上和物理上提供 忠实的平台以实验为基础，以告知未来的预防和治疗 神经退行性疾病的干预措施。