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 阿尔茨海默病 (AD) 和帕金森病会导致进行性退化和 神经细胞（神经元）死亡，损害运动和/或心理功能。 AD 的关键生物标志物，包括淀粉样蛋白 (Aβ) 和 tau 聚集体，已被提出 作为触发可能导致 AD 的神经退行性变的可能机制。 然而，人们对运输和运输的定量和机制了解很少甚至没有。 人们认为这种清除是从大脑中清除小分子、团聚物和碎片。 通过脑脊液（CSF）和间质的全脑血管周围通路发生 液体（ISF）交换，称为类淋巴系统的运输特征。 目前有限，但是经过充分验证的 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。 该提案是开发基于图像的计算建模的集成工具集 描述经过实验参数化和验证的特定受试者的类淋巴运输。 我们提出了一种新颖的方法，使用浸入式等几何方法，其中传输 模型直接根据 3D 成像数据构建，从而产生灵活的、针对特定主题的模型 考虑解剖几何和异质材料特性的模型。 初步研究表明，脑脊液流速等传输参数起着很大的作用 我们勇敢地承认，1）携带淀粉样蛋白的小鼠在类淋巴系统中表现出差异。 功能，包括脑脊液流速，这会导致 Aβ 沉积，并且 2) 增加运动 在淀粉样蛋白沉积的小鼠模型中，将改善类淋巴功能并减少淀粉样蛋白 因此，主要目标是 1) 参数化特定主题的 3D 模型。 类淋巴运输并研究病理条件下蛋白质的全脑沉积 携带淀粉样蛋白的小鼠，2) 模拟运动对类淋巴运输的影响和 随后的淀粉样蛋白沉积。我们先进的类淋巴运输图像引导建模。 与实验紧密结合，并根据特定主题的属性进行调整，提供了独特的 有机会定量评估类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类淋巴功能和蛋白质沉积。 拟议的研究意义重大，因为它将提供建筑学和生理学方面的研究 忠实的平台，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。