Role of the novel entry factor Lrp1 in in vivo tropism and pathogenesis of Rift Valley fever virus
新型进入因子Lrp1在裂谷热病毒体内趋向性和发病机制中的作用
基本信息
- 批准号:10286235
- 负责人:
- 金额:$ 24.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-07 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenovirusesAffectAfricaAlbuminsAnimal ModelAnimalsBindingBiologicalBunyaviridaeCD209 geneCRISPR/Cas technologyCategory A pathogenCattleCell Surface ReceptorsCellsCessation of lifeClinicalCollaborationsCountryCulicidaeDataDiseaseEmerging Communicable DiseasesEncephalitisEnterobacteria phage P1 Cre recombinaseEpidemicGene DeletionGeneticGlycoproteinsGoalsHamstersHeparitin SulfateHepatocyteHeterozygoteHumanIn VitroInfectionInjectionsInsectaIntegration Host FactorsKnock-outKnockout MiceKnowledgeLDL-Receptor Related Protein 1LectinLethal Dose 50LipidsLiverLiver diseasesLivestockLoxP-flanked alleleMediatingMolecularMolecular ChaperonesMonkeysMouse StrainsMusMyelogenousMyeloid CellsNational Institute of Allergy and Infectious DiseaseNeuronsOutcomePathogenesisPathogenicityPathway interactionsProteinsReadinessReagentReceptor CellRetinitisRift Valley fever virusRoleSaudi ArabiaSheepSurfaceSurvivorsTechniquesTestingTissuesTropismVaccinesViral Hemorrhagic FeversViral Load resultViral PathogenesisVirulentVirusVirus DiseasesWorld Health OrganizationZoonosesbasecell typeconditional knockoutgenome-wideglobal healthhepatic necrosishigh rewardhigh riskin vivoinnovationknockout genelipid metabolismmosquito-bornemouse modelnervous system disordernovelpathogenprogramspromoterpublic health emergencyreceptorreceptor expressionrecombinase-mediated cassette exchangesocioeconomicstransmission processvirus tropism
项目摘要
PROJECT SUMMARY/ABSTRACT
The World Health Organization warns of a pending public health emergency caused by mosquito-borne
Rift Valley fever virus (RVFV). RVF is an important disease of domesticated livestock that is zoonotically
transmitted to people, where it causes a spectrum of illness from mild to lethal. The significance of RVFV is
highlighted by its designation as a NIAID Category A pathogen and its inclusion on the WHO's Blueprint of
Priority Diseases, emphasizing the potential impact of RVFV on the global health and economy. Little is known
about the entry factors that RVFV uses to infect cells from multiple species. Our rigorous and convincing
preliminary data identify a cell surface receptor in the host lipid metabolism pathway that mediates infection of
cells by RVFV. This proposal will determine the biological significance of this lipid receptor protein in RVFV
disease in mice through conditional knockouts in cell types that are relevant to RVFV infection, including
hepatocytes, neurons, and myeloid cells. We will use transient and genetic tissue-specific conditional gene
knockouts of the lipid receptor generated using the Cre/Lox system. We hypothesize that eliminating lipid
receptor expression in the liver will rescue mice from an otherwise highly lethal infection. We further hypothesize
that conditional and tissue-specific gene deletions of the lipid receptor in mice will limit RVFV-associated
pathogenic outcomes, including hepatic disease and encephalitis. Our highly collaborative and synergistic team
is led by Dr. Amy Hartman (PI), an expert in the pathogenesis of RVFV, and by Dr. Gaya Amarasinghe (Co-I), a
biochemist and biophysicist with expertise in host-pathogen interactions. This R21 proposal presents an
opportunity to expand upon our collaborative efforts to determine the biological relevance of the RVFV-lipid
receptor interaction in the mouse model. Completion of this proposal will have high impact on the field because
it is the first in vivo assessment of receptor usage by RVFV. All reagents are available including mouse strains,
viruses, and techniques; thus, the feasibility is high.
项目总结/摘要
世界卫生组织警告说,由蚊子传播的
裂谷热病毒(RVFV)。裂谷热是家畜的一种重要疾病,
传播给人类,在那里它会导致一系列从轻微到致命的疾病。RVFV的意义在于
它被指定为NIAID A类病原体,并被列入世界卫生组织的蓝图,
重点疾病,强调RVFV对全球健康和经济的潜在影响。知之甚少
RVFV用来感染多个物种细胞的进入因子。我们的严谨和令人信服的
初步数据确定宿主脂质代谢途径中的细胞表面受体,其介导
细胞RVFV。这一建议将确定该脂质受体蛋白在RVFV中的生物学意义
通过在与RVFV感染相关的细胞类型中的条件性敲除,
肝细胞、神经元和骨髓细胞。我们将使用瞬时的和遗传的组织特异性条件基因
使用Cre/Lox系统产生的脂质受体的敲除。我们假设消除脂质
受体在肝脏中的表达将使小鼠免于高致死性感染。我们进一步假设
小鼠中脂质受体的条件性和组织特异性基因缺失将限制RVFV相关的
致病结果,包括肝病和脑炎。我们高度协作和协同的团队
由RVFV发病机理专家Amy Hartman博士(PI)和RVFV研究专家Gaya Amarasinghe博士(Co-I)领导。
具有宿主-病原体相互作用方面的专业知识的生物化学家和生物药理学家。该R21提案提出了一个
有机会扩大我们的合作努力,以确定RVFV-脂质的生物相关性,
受体相互作用的小鼠模型。完成本提案将对现场产生重大影响,因为
这是RVFV对受体利用的首次体内评估。所有试剂都可用,包括小鼠品系,
病毒和技术;因此,可行性高。
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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Amy L Hartman其他文献
Amy L Hartman的其他文献
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{{ truncateString('Amy L Hartman', 18)}}的其他基金
Mechanisms of Neuronal Infection by Prototype Emerging Bunyaviruses
原型新兴布尼亚病毒感染神经元的机制
- 批准号:
10728597 - 财政年份:2023
- 资助金额:
$ 24.7万 - 项目类别:
Comparative Analysis of Bunyavirus Neuropathogenesis
布尼亚病毒神经发病机制的比较分析
- 批准号:
10675190 - 财政年份:2022
- 资助金额:
$ 24.7万 - 项目类别:
Role of the novel entry factor Lrp1 in in vivo tropism and pathogenesis of Rift Valley fever virus
新型进入因子Lrp1在裂谷热病毒体内趋向性和发病机制中的作用
- 批准号:
10447151 - 财政年份:2021
- 资助金额:
$ 24.7万 - 项目类别:
Live-attenuated Rift Valley fever vaccines: comparative mechanisms of trans-placental transmission and vaccine efficacy for developing fetuses
裂谷热减毒活疫苗:经胎盘传播的比较机制和疫苗对发育中胎儿的功效
- 批准号:
10356824 - 财政年份:2020
- 资助金额:
$ 24.7万 - 项目类别:
Live-attenuated Rift Valley fever vaccines: comparative mechanisms of trans-placental transmission and vaccine efficacy for developing fetuses
裂谷热减毒活疫苗:经胎盘传播的比较机制和疫苗对发育中胎儿的功效
- 批准号:
10673312 - 财政年份:2020
- 资助金额:
$ 24.7万 - 项目类别:
Live-attenuated Rift Valley fever vaccines: comparative mechanisms of trans-placental transmission and vaccine efficacy for developing fetuses
裂谷热减毒活疫苗:经胎盘传播的比较机制和疫苗对发育中胎儿的功效
- 批准号:
10113532 - 财政年份:2020
- 资助金额:
$ 24.7万 - 项目类别:
Neuroprotective anti-inflammatory drugs as a novel combination therapy for neurological Rift Valley Fever
神经保护性抗炎药物作为神经裂谷热的新型联合疗法
- 批准号:
9915980 - 财政年份:2017
- 资助金额:
$ 24.7万 - 项目类别:
Mechanisms of Neuropathogenic Rift Valley Fever in a Novel Rat Model
新型大鼠模型中神经致病性裂谷热的机制
- 批准号:
9002103 - 财政年份:2015
- 资助金额:
$ 24.7万 - 项目类别:
Mechanisms of Neuropathogenic Rift Valley Fever in a Novel Rat Model
新型大鼠模型中神经致病性裂谷热的机制
- 批准号:
8891769 - 财政年份:2015
- 资助金额:
$ 24.7万 - 项目类别:
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