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.

翻译后摘要：估计有650万美国人患有神经退行性疾病，如 阿尔茨海默氏病（AD）和帕金森氏病导致进行性变性， 神经细胞（神经元）死亡，损害运动和/或精神功能。清除延迟 AD的关键生物标志物，包括淀粉样蛋白β（A β）和tau聚集体， 作为一种可能的机制，触发神经变性，可能导致AD。到目前为止， 然而，很少或根本没有定量和机械的了解运输， 从脑中清除小分子、团块和碎片。这种清除被认为是 通过脑脊液（CSF）和间质的全脑血管周围通路发生 流体（ISF）交换，称为胶质淋巴系统。胶质淋巴转运的表征 目前是有限的，然而，经过充分验证的3D计算模型可以实现量化 关键AD生物标志物在整个大脑中的运输和清除。的长期目标 该建议是开发基于图像的计算建模的集成工具集， 描述了实验参数化和验证的受试者特异性胶质淋巴转运。 我们提出了一种新的方法，使用浸没等几何方法，其中运输 直接从3D成像数据构建模型，从而产生灵活的、特定于对象的 考虑解剖学几何结构和异质材料特性的模型。我们 初步研究表明，脑脊液流速等转运参数在脑脊髓损伤中起着重要作用 A β沉积。我们假设：1）携带淀粉样蛋白的小鼠在胶质淋巴细胞中表现出差异， 功能，包括CSF流速，导致A β沉积和2）增加运动 在淀粉样蛋白沉积小鼠模型中， 证词因此，主要目标是1）参数化特定于主题的3D模型 胶质淋巴运输和研究在病理条件下蛋白质的全脑沉积， 携带淀粉样蛋白的小鼠，和2）模拟运动对胶质淋巴转运的影响， 随后淀粉样蛋白沉积。我们先进的胶质淋巴转运图像引导建模 与实验紧密结合，并根据特定主题的属性进行调整， 有机会定量评估胶质淋巴功能障碍对废物清除的影响， 研究运动等特定因素如何驱动胶质淋巴功能和蛋白质沉积。的 拟议的研究是重要的，因为它将提供一个建筑和生理 可靠的平台，以实验为基础，为未来的预防和治疗提供信息 神经退行性疾病的干预措施。