Prion Transport Across the Blood-Brain Barrier

朊病毒跨血脑屏障运输

基本信息

批准号：
7276564
负责人：
WILLIAM A BANKS
金额：
$ 30.84万
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/7276564
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

DESCRIPTION (provided by applicant): 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 BBB through 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.

描述（由申请人提供）：病毒疾病代表了一群多样的感染性神经退行性疾病。最接受的假设是传染剂（称为prion）是完全没有核酸的正常蛋白的错误折叠版本。当传染性形式（PRPSC）通过可逆地结合使用传染性形式（PRPSC）将正常形式（PRPC）转化为传染性形式时，疾病就会传播。在crapie中，prion是一种糖蛋白，约有30,000兆瓦的蛋白质核。为了产生中枢神经系统（CNS）疾病，PRPSC必须进入大脑，这需要协商血脑屏障（BBB）。这项研究的主要目的是确定PRPSC如何跨越BBB，并最终制定阻止通过中枢神经系统通过的治疗策略，从而防止prion病。我们和其他人的作用表明，其他神经毒性糖蛋白（例如小麦凝集素和gp120，艾滋病病毒的涂层）通过诱导吸收性内吞作用（AE）穿越BBB。我们假设PRPSC通过AE的机制越过BBB。该假设提供了一种通过无细胞PRPSC和PRPSC感染的免疫细胞BBB传递的机制，并解释了如何特别针对CNS的某些CNS区域（例如胸部脊髓）。尽管我们的工作假设是无细胞的PRPSC是主要机制，但这些实验旨在确定进入CNS的其他可能机制的程度（免疫细胞转移，逆行脾神经传递，跨膜扩散，可饱和载体/可饱和载体/可饱和载体/受体介导的运输，通过细胞外途径泄漏）对PRPSC进行操作。我们将使用高度纯净的放射性标记的PRPSC来确定转运和分布到大脑区域，脊髓和CSF，脾神经和免疫细胞在神经侵袭中的作用，以及在体外模型中检查跨过跨过的细胞生物学脑内皮细胞。摘要：王室会导致罕见但毁灭性的疾病，例如疯牛病。为了引起疾病，王室必须越过血脑屏障才能进入大脑。我们将确定Prions如何穿越BBB。知道王室如何进入大脑应该导致有关如何预防病毒疾病的策略。