Probing prion clearance through interstitial fluid and perivascular pathways

通过间质液和血管周围途径探测朊病毒清除率

基本信息

批准号：
9789974
负责人：
Christina Sigurdson
金额：
$ 19.69万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789974
关键词：
Affect Alzheimer&apos s Disease Amyloid beta-Protein Amyotrophic Lateral Sclerosis Astrocytes Blood Blood - brain barrier anatomy Blood Vessels Brain Brain region Carotid Artery Ulcerating Plaque Carrier Proteins Cessation of life Cognitive Creutzfeldt-Jakob Syndrome Diffuse Disease Disease Progression Drainage procedure Extracellular Fluid Extracellular Space Genetic Goals Heparitin Sulfate Human Impairment Infection Intercellular Fluid Lead Length Liquid substance Metabolic Molecular Conformation Motor Mus Neurodegenerative Disorders Parkinson Disease Pathway interactions Patients Play PrP PrPSc Proteins Prion Diseases Prions Proteins Role Stroke Structure Suggestion Symptoms Tauopathies Testing Time Traumatic Brain Injury Waste Products Water Water Movements Work aquaporin 4 astrogliosis conformer density disease phenotype extracellular fluid flow foot improved in vivo insight interstitial mouse model neuron loss new therapeutic target prion-like protein aggregate protein transport solute syntrophin alpha1 wasting water channel

项目摘要

Prion diseases are neurodegenerative disorders characterized by rapid cognitive and motor decline. Similar to amyloid-β in Alzheimer’s disease, certain prion aggregates spread through the brain and accumulate as parenchymal and vascular plaques. We hypothesize that prions, similar to amyloid-β, can transit through the interstitial fluid for clearance in perivascular channels. We recently found that shortening heparan sulfate chain length in mice reduced parenchymal prion plaques yet increased vascular plaques in the brain, consistent with improved prion clearance through the interstitial fluid (ISF). Survival time was also prolonged. We and others also recently found that the water transport protein, aquaporin 4, redistributes from astrocyte end feet in prion-affected blood vessels, indicating alterated perivascular channels in prion disease. In addition, aquaporin 4 expression is elevated in prion disease. In Aim 1, we will define when and how vascular channels and the blood brain barrier are modified during prion disease in humans and mice. In Aim 2, we will employ genetic mouse models with impaired CSF-ISF exchange to determine how impairing fluid exchange impacts prion disease progression and phenotype. We will also establish the prion conformers that most severely modify water channel transport proteins, CSF-ISF fluid exchange, and the blood brain barrier in humans and in mice.

朊病毒病是一种神经退行性疾病，其特征是快速和运动性与阿尔茨海默氏病中的β淀粉样蛋白类似，某些朊病毒聚集体通过大脑扩散。大脑并以实质和血管斑块的形式积累，我们捕获了类似的朊病毒。淀粉样蛋白-β，可以通过间质液转运以在血管周围通道中清除。最近发现，缩短小鼠体内的硫酸乙酰肝素链长度可减少实质朊病毒斑块但大脑中血管斑块增加，与朊病毒清除率的改善一致我们和其他人最近也延长了通过间质液（ISF）的存活时间。发现水转运蛋白水通道蛋白 4 在受朊病毒影响的血管中从星形胶质细胞末端重新分布，表明朊病毒疾病的血管周围通道发生了改变。水通道蛋白 4 的表达在朊病毒病中升高。在目标 1 中，我们将定义何时以及如何升高。人类的血管通道和血脑屏障在朊病毒病期间发生改变在目标 2 中，我们将采用 CSF-ISF 交换受损的遗传小鼠模型来进行实验。确定液体交换受损如何影响朊病毒疾病的进展和表型。还将建立最严重改变水道运输的朊病毒构象异构体蛋白质、CSF-ISF 液体交换以及人类和小鼠的血脑屏障。