Prion Transport Across the Blood-Brain Barrier

描述(由申请人提供)：Pron疾病代表一组不同的感染性神经退行性疾病。最被接受的假设是，感染性病原体(称为Prion)是完全不含核酸的正常蛋白质的错误折叠版本。当感染形式(PrPsc)通过可逆结合将正常形式(PrPc)转换为感染形式时，疾病就会传播。在瘙痒病中，Prion是一种糖蛋白，核心蛋白约为30,000 mW。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是如何穿过血脑屏障的，并最终开发出阻断进入中枢神经系统的通道从而预防Prion疾病的治疗策略。我们和其他人的工作表明，其他神经毒性糖蛋白(如麦芽凝集素和艾滋病病毒外壳gp120)通过诱导吸收内吞作用(AE)跨越血脑屏障。我们假设PrPsc通过AE机制穿过血脑屏障。这一假说为无细胞PrPsc和感染PrPsc的免疫细胞穿过血脑屏障提供了一种机制，并解释了为什么中枢神经系统的某些区域，如胸髓，可以特别成为靶点。虽然我们的工作假设是无细胞PrPsc是PrPsc的主要机制，但这些实验旨在确定其他可能进入中枢神经系统的机制(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)在多大程度上适用于PrPsc。我们将使用高纯度、放射性标记的PrPsc来确定运输和分布到脑区、脊髓和脑脊液的速率，确定脾神经和免疫细胞在神经侵袭中的作用，并在体外模型中检查穿过脑内皮细胞的细胞生物学。普鲁士摘要：普里恩引起罕见但毁灭性的疾病，如疯牛病。为了致病，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。

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.