Prion Transport Across the Blood-Brain Barrier
Prion Transport Across the Blood-Brain Barrier
批准号:
7576780
负责人:
WILLIAM A BANKS
金额:
$30.89万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2006
资助国家:
美国
项目状态:
已结题
起止时间:
2006-08-15 至 2011-01-31
关键词:
AgglutininsAmino AcidsAttentionAutoradiographyBindingBloodBlood - brain barrier anatomyBlood VesselsBlood capillariesBovine Spongiform EncephalopathyBrainBrain regionCell membraneCell physiologyCellsCellular biologyCentral Nervous System DiseasesCerebrospinal FluidCharacteristicsChestClinicalCore ProteinDependenceDetergentsDiffusionDiseaseEndocytosisEndothelial CellsEpendymal CellExtravasationGlycoproteinsGoalsGolgi ApparatusHIVHIV Envelope Protein gp120HamstersHigh Pressure Liquid ChromatographyImmuneIn VitroInfectionInfectious AgentIntercellular FluidKineticsLabelLeadLysosomesMeasuresMediatingMediationModelingModificationMusNerveNeuraxisNeurodegenerative DisordersNucleic AcidsOligosaccharidesP-GlycoproteinP-GlycoproteinsPathway interactionsPeptide HydrolasesPermeabilityPrion DiseasesPrionsProteinsPublishingRadioactivityRecombinantsRegression AnalysisResearchResearch PersonnelResistanceRoleRouteSCID MiceSamplingScrapieSialic AcidsSideSolubilitySpecies SpecificitySpinal CordStructureStructure of choroid plexusSurfaceTestingTherapeuticThoracic spinal cord structureTight JunctionsTimeVertebral columnVesicleVirusWorkabsorptive endocytosisbasecapillarycapillary beddesignextracellularglycosylationin vitro Modelin vivoinhibitor/antagonistneurotoxicneurotransmissionpreventprogramsreceptorresearch studytranscytosis
中文摘要
朊病毒疾病代表了一组不同的传染性神经退行性疾病。接受度最高的
一种假说认为,感染因子(称为朊病毒)是一种正常蛋白质的错误折叠形式,
缺乏核酸的。当传染性形式(PrPsc)转化为正常形式时,
在羊瘙痒病中,朊病毒是一种糖蛋白,
30,000兆瓦的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)。本研究的主要目的是确定
PrPsc如何穿过血脑屏障,并最终开发出阻断进入血脑屏障的治疗策略。
从而预防朊病毒病。我们和其他人的工作表明,
糖蛋白(如小麦胚芽凝集素和gp 120,艾滋病病毒的外壳)通过血脑屏障,
诱导吸收性内吞作用(AE)。我们假设PrPsc通过以下机制穿过BBB:
的AE。该假设提供了无细胞PrPsc和PrPsc通过BBB的机制。
感染的免疫细胞,并解释了如何中枢神经系统的某些区域,如胸脊髓,可以
尤其是针对。虽然我们的工作假设是无细胞PrPsc是主要机制,但这些研究表明,
实验的目的是确定在何种程度上进入的其他可能的机制,
CNS(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)对于PrPsc是可操作的。我们将
使用高度纯化、放射性标记的PrPsc测定转运和分布到脑中的速率
区域,脊髓和CSF,脾神经和免疫细胞在神经侵袭中的作用,以及体外
模型来检查穿过脑内皮细胞的细胞生物学。
摘要:朊病毒引起罕见的,但毁灭性的疾病,如疯牛病。引起疾病,
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。
了解了朊病毒如何进入大脑,就可以制定出预防朊病毒疾病的策略。
英文摘要
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.
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DOI:
10.3233/jad-2009-1074
发表时间:
2009
期刊:
Journal of Alzheimer's disease : JAD
影响因子:
--
作者:
[Jaeger LB, Dohgu S, Hwang MC, Farr SA, Murphy MP, Fleegal-DeMotta MA, Lynch JL, Robinson SM, Niehoff ML, Johnson SN, Kumar VB, Banks WA]
通讯作者:
Banks WA
DOI:
10.1007/s11481-008-9138-y
发表时间:
2009-06
期刊:
JOURNAL OF NEUROIMMUNE PHARMACOLOGY
影响因子:
6.2
作者:
[Salkeni, Mohamad A., Lynch, Jessica L., Otamis-Price, Tulin, Banks, William A.]
通讯作者:
Banks, William A.
DOI:
10.1016/j.bbi.2009.01.017
发表时间:
2009-05
期刊:
BRAIN BEHAVIOR AND IMMUNITY
影响因子:
15.1
作者:
[Jaeger, Laura B., Dohgu, Shinya, Sultana, Rukhsana, Lynch, Jessica L., Owen, Joshua B., Erickson, Michelle A., Shah, Gul N., Price, Tulin O., Fleegal-Demotta, Melissa A., Butterfiled, D. Allan, Banks, William A.]
通讯作者:
Banks, William A.
DOI:
10.1186/1742-2094-8-167
发表时间:
2011-11-30
期刊:
Journal of neuroinflammation
影响因子:
9.3
作者:
[Dohgu S, Fleegal-DeMotta MA, Banks WA]
通讯作者:
Banks WA
DOI:
10.1016/j.bbadis.2009.10.011
发表时间:
2010-10
期刊:
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
影响因子:
6.2
作者:
[Banks, William A.]
通讯作者:
Banks, William A.
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