Prion Transport Across the Blood-Brain Barrier

朊病毒跨血脑屏障运输

基本信息

批准号：
7415072
负责人：
WILLIAM A BANKS
金额：
$ 30.86万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7415072
关键词：
Agglutinins Amino Acids Attention Autoradiography Binding Blood Blood - brain barrier anatomy Blood Vessels Blood capillaries Bovine Spongiform Encephalopathy Brain Brain region Cell membrane Cell physiology Cells Cellular biology Central Nervous System Diseases Cerebrospinal Fluid Characteristics Chest Clinical Core Protein Dependence Detergents Diffusion Disease Endocytosis Endopeptidases Endothelial Cells Ependymal Cell Extravasation Glycoproteins Goals Golgi Apparatus HIV HIV Envelope Protein gp120 HIV-1 Hamsters High Pressure Liquid Chromatography Immune In Vitro Infection Infectious Agent Intercellular Fluid Kinetics Label Lead Lysosomes Measures Mediating Mediation Modeling Modification Mus Nerve Neuraxis Neurodegenerative Disorders Nucleic Acids Oligosaccharides P-Glycoprotein P-Glycoproteins Pathway interactions Peptide Hydrolases Permeability Prion Diseases Prions Proteins Publishing Radioactivity Rate Recombinants Regression Analysis Research Research Personnel Resistance Role Route SCID Mice Sampling Scrapie Sialic Acids Side Solubility Species Specificity Spinal Cord Structure Structure of choroid plexus Surface Testing Therapeutic Thoracic spinal cord structure Tight Junctions Time Vertebral column Vesicle Virus Work absorptive endocytosis base capillary capillary bed design extracellular glycosylation in vitro Model in vivo inhibitor/antagonist neurotoxic neurotransmission prevent programs receptor research study transcytosis

项目摘要

Prion diseases represent a diverse group of infectious neurodegenerative disorders. The most accepted hypothesis is that the infectious agent (termed prion) is a misfolded version of a normal protein completely devoid of nucleic acids. Disease is propagated when the infectious form (PrPsc) converts the normal form (PrPc) to the infectious form by reversibly combining with it. In scrapie, the prion is a glycoprotein with about a 30,000 MW protein core. To produce central nervous system (CNS) disease, PrPsc must enter the brain, which requires it negotiate the blood-brain barrier (BBB). The major goal of this research is to determine how PrPsc crosses the BBB and ultimately to develop therapeutic strategies for blocking passage into the CNS and so preventing prion disease. Work by us and others have shown that other neurotoxic glycoproteins (such as wheatgerm agglutinin and gp120, the coat of the AIDS virus) cross the BBB by inducing absorptive endocytosis (AE). We hypothesize that PrPsc crosses the BBBthrough the mechanism of AE. This hypothesis provides a mechanism for passage across the BBB of cell-free PrPsc and of PrPsc- infected immune cells and explains how some regions of the CNS, such as the thoracic spinal cord, can be especially targeted. Although our working hypothesis is that cell-free PrPsc is the major mechanism , these experiments are designed to determine the extent to which the other possible mechanisms of entry into the CNS (immune cell transfer, retrograde splenic nerve transmission, transmembrane diffusion, saturable carrier/receptor mediated transport, leakage via extracellular pathways) are operational for PrPsc. We will use highly purified, radioactively labeled PrPsc to determine rates of transport and distribution into brain regions, spinal cord, and CSF, the role of splenic nerves and immune cells in neuroinvasion, and in vitro models to examine the cellular biology of passage across the brain endothelial cell. Lay Summary: Prions cause rare, but devastating, diseases such as mad cow disease. To cause disease, prions must cross the blood-brain barrier to enter the brain. We will determine how prions cross the BBB. Knowing how prions enter the brain should lead to strategies on how to prevent prion diseases.

朊病毒病代表了多种传染性神经退行性疾病。最受接受的假设感染因子（称为朊病毒）是正常蛋白质完全错误折叠的版本不含核酸。当传染性形式 (PrPsc) 转变为正常形式时，疾病就会传播 (PrPc)通过与其可逆地结合而转变为传染性形式。在痒病中，朊病毒是一种糖蛋白，其含 30,000 MW 蛋白质核心。要产生中枢神经系统 (CNS) 疾病，PrPsc 必须进入大脑，这需要它通过血脑屏障（BBB）。这项研究的主要目标是确定 PrPsc 如何穿过 BBB 并最终制定阻断进入 BBB 的治疗策略预防中枢神经系统朊病毒病等。我们和其他人的工作表明，其他神经毒性物质糖蛋白（例如麦芽凝集素和 gp120，艾滋病病毒的外壳）通过 BBB 诱导吸收性内吞作用（AE）。我们假设 PrPsc 通过以下机制穿过 BBB AE。这一假说提供了一种无细胞 PrPsc 和 PrPsc-穿过 BBB 的机制。感染的免疫细胞并解释了中枢神经系统的某些区域（例如胸脊髓）是如何被感染的特别有针对性。尽管我们的工作假设是无细胞 PrPsc 是主要机制，但这些实验的目的是确定其他可能的进入机制的程度 CNS（免疫细胞转移、逆行脾神经传递、跨膜扩散、可饱和载体/受体介导的运输、通过细胞外途径的渗漏）对于 PrPsc 来说是可操作的。我们将使用高度纯化、放射性标记的 PrPsc 来确定进入大脑的运输和分布速率区域、脊髓和脑脊液，脾神经和免疫细胞在神经侵袭中的作用，以及体外用于检查穿过脑内皮细胞的细胞生物学的模型。外行总结：朊病毒会导致罕见但具有毁灭性的疾病，例如疯牛病。导致疾病，朊病毒必须穿过血脑屏障才能进入大脑。我们将确定朊病毒如何穿过血脑屏障。了解朊病毒如何进入大脑应该有助于制定预防朊病毒疾病的策略。