Key molecular mechanisms of extraneural pathogenesis and transmission of TSEs
TSE 神经外发病机制和传播的关键分子机制
基本信息
- 批准号:8098715
- 负责人:
- 金额:$ 27.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-07-01 至 2013-06-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAffectAnimal ModelAnimalsBackcrossingsBindingBiochemicalBovine Spongiform EncephalopathyCattleChronic Wasting DiseaseColoradoCommunicable DiseasesComplementComplement 1qComplement 3d ReceptorsCreutzfeldt-Jakob SyndromeDataDeerDiseaseDisease ProgressionDisease modelDoseEarly DiagnosisEarly treatmentEndopeptidase KEngineeringEnsureEquine muleEventExhibitsExperimental ModelsFood SupplyFutureGenetic TechniquesGoalsHealthHumanImmunologyIndividualInfectionInfectious AgentIngestionInvestigationKnockout MiceKnowledgeKuruLeftLigandsLymphoidLymphoid TissueMapsMethodsModelingMolecularMusNervous system structureOrganPathogenesisPeripheralPopulationPrPPrPCWDPrPSc ProteinsPredispositionPrevalencePrion DiseasesPrionsProcessPublic HealthPublishingResearchResistanceRiskRoleSafetyScrapieSheepSiteTestingTropismWorkbasecervidchronic wasting disease of elk and deercobra venom factorcomplement systemdesigndomain mappingeconomic impactmouse modelmutantnoveloffspringpreventresearch studytooltransmission process
项目摘要
DESCRIPTION (provided by applicant): Prion diseases are invariably fatal infectious diseases affecting a wide range of animals. These include chronic wasting disease (CWD) of deer and elk, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jacob disease and kuru in humans. CWD appears to be especially contagious, with suspected horizontal transfer efficiency reaching 90% and estimates of infection among mule deer populations in Colorado reaching 20%. Possible transfer to humans, as exhibited for BSE, has not been systematically disproven and the accompanying risk to public health remains. Moreover, if left unchecked, the ecologic and economic impact could be devastating. Our long-term goals include developing mouse models of CWD to elucidate the molecular mechanisms involved in extraneural prion dissemination, accumulation and replication. We also plan to further our understanding of these processes using novel as well as established mouse models of scrapie, with the ultimate goal of developing further CWD models in mice based on these data. Our specific hypothesis states that certain components of the Complement system enable optimal prion capture, replication and neuroinvasion in CWD and scrapie. We derive this hypothesis from 1) previously published data demonstrating that partial or complete depletion of Complement components C1q, C3 and CD21 delays splenic prion accumulation and replication; and impedes or even prevents disease in murine models of scrapie; and 2) previously published data showing significant PrPCWD localization in CD21-expressing lymphoid tissue from deer and 3) our current data that shows murine CD21/35 interacts with PrPSc without its endogenous ligands C3 and C4. We plan to extend this work and initiate new investigations with the following specific aims: 1) Test Complement-deficient Tg(CerPrP) mouse models. 2) Test the horizontal transmissibility of CWD in Tg(cerPrP) mice. 3) Extend our investigation into the role of Complement in peripheral prion pathogenesis using murine scrapie models. Our data strongly suggest that PrPSC can interact with sites on CD21/35 distinct from those that bind C3 cleavage products. We will map these sites by creating CD21/35 truncation mutants and analyzing their ability to bind PrPSc and PrPCWD. PUBLIC HEALTH RELEVANCE: Interspecies transmission from BSE-infected cattle in the UK to humans has almost certainly occurred, and has not been disproved for other TSEs, including scrapie and CWD. Determining mechanisms of transmission of scrapie and CWD, which exhibit incredibly efficient Intraspecies transmission, is vital to ensuring the safety of the nation's food supply and, therefore, public health.
描述(由申请人提供):朊病毒疾病是影响广泛动物的致命传染病。这些疾病包括鹿和麋鹿的慢性消耗性疾病(CWD)、羊的痒病、牛的牛海绵状脑病(BSE)以及人类的克雅氏病和库鲁病。CWD似乎具有特别的传染性,疑似水平传播效率达到90%,科罗拉多州骡鹿种群的感染率估计达到20%。疯牛病可能向人类传播的事实尚未得到系统的反驳,对公共卫生的伴随风险仍然存在。此外,如果不加以控制,对生态和经济的影响可能是毁灭性的。我们的长期目标包括建立CWD小鼠模型,以阐明神经外朊病毒传播、积累和复制的分子机制。我们还计划使用新的和已建立的瘙痒小鼠模型来进一步了解这些过程,最终目标是基于这些数据开发进一步的小鼠CWD模型。我们的具体假设表明,补体系统的某些组成部分能够在CWD和痒病中实现最佳的朊病毒捕获、复制和神经侵袭。我们的假设来源于:1)先前发表的数据表明补体成分C1q、C3和CD21的部分或完全耗竭会延缓脾朊病毒的积累和复制;在小鼠痒病模型中阻碍甚至预防疾病;2)先前发表的数据显示,PrPCWD在鹿的cd21表达淋巴组织中有显著的定位;3)我们目前的数据显示,小鼠的CD21/35与PrPSc相互作用,没有内源性配体C3和C4。我们计划扩展这项工作并开展新的研究,具体目标如下:1)测试补体缺陷Tg(CerPrP)小鼠模型。2)检测CWD在Tg(cerPrP)小鼠体内的水平传播率。3)利用小鼠痒病模型进一步研究补体在外周朊病毒发病机制中的作用。我们的数据强烈表明,PrPSC可以与CD21/35上的位点相互作用,而不是与C3切割产物结合的位点。我们将通过创建CD21/35截断突变体并分析其结合PrPSc和PrPCWD的能力来绘制这些位点。公共卫生相关性:在英国,从感染疯牛病的牛到人类的种间传播几乎肯定发生过,并且在其他tse(包括痒病和CWD)中没有被反驳。痒病和CWD表现出令人难以置信的物种内传播效率,确定其传播机制对于确保国家食品供应安全以及公共卫生至关重要。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MARK D ZABEL其他文献
MARK D ZABEL的其他文献
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{{ truncateString('MARK D ZABEL', 18)}}的其他基金
Liposome-siRNA-Peptide Complexes as Therapy to Cure Prion Diseases in Mouse Model
脂质体-siRNA-肽复合物作为治疗小鼠模型中朊病毒病的疗法
- 批准号:
8616817 - 财政年份:2012
- 资助金额:
$ 27.97万 - 项目类别:
Liposome-siRNA-Peptide Complexes as Therapy to Cure Prion Diseases in Mouse Model
脂质体-siRNA-肽复合物作为治疗小鼠模型中朊病毒病的疗法
- 批准号:
8294338 - 财政年份:2012
- 资助金额:
$ 27.97万 - 项目类别:
Liposome-siRNA-Peptide Complexes as Therapy to Cure Prion Diseases in Mouse Model
脂质体-siRNA-肽复合物作为治疗小鼠模型中朊病毒病的疗法
- 批准号:
9013506 - 财政年份:2012
- 资助金额:
$ 27.97万 - 项目类别:
Liposome-siRNA-Peptide Complexes as Therapy to Cure Prion Diseases in Mouse Model
脂质体-siRNA-肽复合物作为治疗小鼠模型中朊病毒病的疗法
- 批准号:
8423314 - 财政年份:2012
- 资助金额:
$ 27.97万 - 项目类别:
Key molecular mechanisms of extraneural pathogenesis and transmission of TSEs
TSE 神经外发病机制和传播的关键分子机制
- 批准号:
7874449 - 财政年份:2008
- 资助金额:
$ 27.97万 - 项目类别:
Key molecular mechanisms of extraneural pathogenesis and transmission of TSEs
TSE 神经外发病机制和传播的关键分子机制
- 批准号:
7526477 - 财政年份:2008
- 资助金额:
$ 27.97万 - 项目类别:
Key molecular mechanisms of extraneural pathogenesis and transmission of TSEs
TSE 神经外发病机制和传播的关键分子机制
- 批准号:
8282869 - 财政年份:2008
- 资助金额:
$ 27.97万 - 项目类别:
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