Prion Transport Across the Blood-Brain Barrier

Pron疾病代表了一组不同的感染性神经退行性疾病。接受程度最高的 假设感染因子(称为普里恩)是正常蛋白质的完全错误折叠版本。 没有核酸的。当传染性形式(PrPsc)转化为正常形式时，疾病就会传播 (PrPC)通过可逆地与其结合而转变为传染性形式。在瘙痒病中，Prion是一种糖蛋白，大约有 3万兆瓦的蛋白质核心。为了产生中枢神经系统(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如何跨越血脑屏障，并最终制定治疗策略，以阻断进入 中枢神经系统等预防普恩病毒疾病。我们和其他人的研究表明，其他神经毒素 糖蛋白(如麦芽凝集素和艾滋病病毒外壳gp120)通过以下途径穿过血脑屏障 诱导吸收内吞作用(AE)。我们假设PrPsc通过这个机制跨越了BBB 阿联酋的。这一假说提供了一种跨越无细胞PrPsc和PrPsc的血脑屏障的机制。 并解释了中枢神经系统的某些区域，如胸髓，如何 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 实验旨在确定其他可能的进入机制的程度 免疫细胞转移，逆行脾神经传递，跨膜扩散，饱和 载体/受体介导的转运、通过细胞外途径的渗漏)对PrPsc是有效的。我们会 使用高纯度的放射性标记PrPsc来确定脑内转运和分布的速率 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 研究穿过大脑内皮细胞的细胞生物学的模型。 普鲁士摘要：普里恩引起罕见但毁灭性的疾病，如疯牛病。来引发疾病， 普恩病毒必须穿过血脑屏障才能进入大脑。我们将确定普里恩如何穿过血脑屏障。 了解普恩病毒是如何进入大脑的，应该会导致如何预防普恩病毒疾病的策略。

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.