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.

病毒疾病是以快速认知和运动为特征的神经退行性疾病衰退。与阿尔茨海默氏病中的淀粉样蛋白β相似，某些prion骨料通过大脑并积聚为副斑块和血管斑块。我们假设该王子，类似到淀粉样蛋白β，可以通过间质液转移以在血管周通道中清除。最近发现，缩短小鼠硫酸乙酰肝素链长度会减少副群素斑块却增加了大脑中的血管斑块，与改善的prion清除一致通过间质流体（ISF）。生存时间也延长了。我们和其他人最近也发现水中通道蛋白4，在受prion影响的血管中从星形胶质细胞末端重新分布，表明prion病中血管周通道改变。此外，在prion病中，水通道蛋白4的表达升高。在AIM 1中，我们将定义何时以及如何血管通道和血脑屏障在人类的prion病期间被修饰老鼠。在AIM 2中，我们将采用CSF-FISF交换受损的基因鼠标模型确定流体交换如何影响prion疾病进展和表型。还将建立最严重修改水通道传输的prion构象体蛋白质，CSF-FISF液交换以及人类和小鼠的血脑屏障。