Interstitial fluid flow in Alzheimer's Disease Progression

阿尔茨海默病进展中的间质液流动

基本信息

批准号：
10185070
负责人：
Jennifer M Munson
金额：
$ 202.2万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10185070
关键词：
3-Dimensional Abeta synthesis Address Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid Amyloid beta-Protein Amyloidosis Animals Astrocytes Binding Biological Models Biomedical Engineering Blood Brain Brain Injuries Brain imaging Cell surface Cells Cellular biology Cerebrospinal Fluid Cerebrovascular system Cleaved cell Cognitive deficits Computational algorithm Computer Models Coupled Development Diagnosis Disease Disease Progression Disease model Drainage procedure Etiology Grant Harvest Health Hippocampus (Brain)Human Hydrogels Impaired cognition Impairment In Vitro Individual Inflammatory Intercellular Fluid J20 mouse Knock-out Late Onset Alzheimer Disease Lead Link Lipids Liquid substance Longitudinal Studies Lymphatic function Malignant Neoplasms Malignant neoplasm of brain Measurement Measures Mediating Mediator of activation protein Memory Loss Meningeal lymphatic system Methods Microfluidics Microglia Microscopy Modality Modeling Molecular Biology Mus Nerve Degeneration Neuroglia Neurons Normal Cell Pathogenesis Pathologic Pathway interactions Pattern Peptides Pharmacology Physiological Production Reporting Risk Factors Role Route Senile Plaques Series Signal Transduction Slice Sphingosine-1-Phosphate Receptor System Therapeutic Tissue Engineering Tissue imaging Tissues Transgenic Mice VEGFC gene Work abeta accumulation abeta deposition apolipoprotein E-4 associated symptom base behavior test brain tissue cancer cell cell motility computer framework design disease phenotype fluid flow genetic risk factor glymphatic system healthy aging high risk human model imaging approach imaging modality in vitro Model in vivo in vivo imaging induced pluripotent stem cell insight interstitial intravital imaging mouse model neurofibrillary tangle formation neurotransmission novel pressure receptor relating to nervous system response shear stress sphingosine 1-phosphate tau aggregation time use trafficking tumor tumor microenvironment

项目摘要

Project Summary Alzheimer's Disease is a devastating disease marked by cognitive decline. The reasons underlying this decline are still unclear, but it is known that Amyloid β (Aβ) aggregation and accumulation in the brain contributes to worsening cognitive deficits. Recently, it has been identified that major mediators of bulk fluid flow in the brain are implicated in the clearing of Amyloid β, including the glymphatic system, the meningeal lymphatics, and the blood vasculature. Decreased fluid flow via any of these routes can worsen accumulation of Aβ and cognitive deficits in murine models of the disease. Bulk pathways are important for understanding overall clearance from the brain, however, it does not give us insight into the underlying cellular or tissue-level mechanisms. Interstitial fluid flow is the flow within tissue around the cells, interacting with each cell surface. These interactions can result in downstream changes to cell signaling inducing activation, inflammatory cascades, and cellular migration. In brain cancer, increased interstitial fluid flow develops due to the increase in interstitial pressure in the tumor bulk interfacing with the relatively normal pressure of the surrounding brain tissue, or tumor microenvironment. In our prior grant, we focused on this increased interstitial flow in brain cancer to identify the mechanisms underlying this flow-mediated invasion. To examine how interstitial fluid flow affects the invasion of brain cancer cells, we have developed in vitro and in vivo methods to examine fluid flow responses including multicellular in vitro tissue engineered systems and in vivo imaging methods. In AD, though flow may be decreasing, the same molecules and mechanisms may be involved due to their flow sensitivity. Thus, in this application, we will conduct direct in vivo measurements of interstitial flow using intravital imaging in mouse models of AD. Using this information we will build our in vitro models of the neuro-glial microenvironment with human and mouse healthy and AD-affected cells to identify the role of IFF in secretion, accumulation, and patterning of Aβ as well as the effect of different types of Aβ and IFF on cellular health. Last, we will determine the role of a unique molecule identified in cancer but expressed on astrocytes and microglia, S1PR3, in mediating the AD phenotype and determine if there is benefit to therapeutically agonizing or antagonizing this receptor to mitigate cognitive deficits. Altogether, these reports will advance the importance and strategies for mitigating interstitial flow and its effects in Alzheimer's Disease and offer modalities by which to study further effects of flow at the cellular level. Understanding the impact of interstitial flow may ultimately help predict, diagnose, and treat Alzheimer's Disease.

项目摘要阿尔茨海默氏病是一种以认知能力下降为特征的毁灭性疾病。这一下降的原因仍然不清楚，但众所周知，淀粉样蛋白β（Aβ）的聚集和大脑中的积累有助于认知缺陷恶化。最近，已经确定了大脑中散装流体流动的主要介体在淀粉样β的清除中暗示，包括糖基体系，脑膜淋巴管和血管系统。通过这些路线中的任何一项，流体流量减少可能会降低Aβ和认知的积累该疾病的鼠模型中的缺陷。批量途径对于理解总体清除很重要但是，大脑并不能让我们深入了解潜在的细胞或组织水平机制。间隙流体流量是细胞周围组织内的流动，与每个细胞表面相互作用。这些相互作用可能导致在下游变化，细胞信号传导引起的激活，炎症级联反应和细胞迁移。脑癌，由于肿瘤散装的间质压力增加而增加的间质流体流动发展与周围脑组织或肿瘤微环境的相对正常压力接口。在我们的事先授予，我们专注于这种增加的脑癌间质性流动，以识别基础机制这种流动介导的入侵。为了检查间质流体流动如何影响脑癌细胞的侵袭，我们已经开发了体外和体内方法，以检查包括多细胞体外组织的流体流动反应工程系统和体内成像方法。在AD中，尽管流量可能正在减少，但相同的分子由于其流动敏感性，可能涉及机制。在此应用程序中，我们将直接进行在AD的小鼠模型中，使用插入式成像对间质流的体内测量。使用此信息我们将与人类和小鼠健康且受ad的影响建立我们的神经胶质微环境的体外模型细胞确定IFF在分泌，积累和Aβ的作用以及不同的作用 Aβ和IFF的类型在细胞健康方面。最后，我们将确定在癌症中鉴定出的独特分子的作用但以星形胶质细胞和小胶质细胞的表达，S1PR3，在介导AD表型并确定是否存在热痛苦或拮抗该受体以减轻认知缺陷的好处。这些，这些报告将提高减轻间质流及其在阿尔茨海默氏症的影响的重要性和策略疾病并提供了研究细胞水平流动进一步影响的方式。了解间质流的影响最终可能有助于预测，诊断和治疗阿尔茨海默氏病。