Genomic and molecular determinants of EV-D68 neuroinvasive disease
EV-D68神经侵袭性疾病的基因组和分子决定因素
基本信息
- 批准号:10657198
- 负责人:
- 金额:$ 38.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-15 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:5&apos Untranslated RegionsAcyclovirAgeAntiviral AgentsApoptosisBrainCentral Nervous SystemCentral Nervous System DiseasesCentral Nervous System InfectionsCentral Nervous System Viral DiseasesCerebrospinal FluidCerebrumCessation of lifeChildClinicalCommunitiesDependenceDevelopmentDiseaseDisease OutbreaksEnterovirusEnterovirus 68EpidemicExperimental ModelsGeneticGenomicsHerpes encephalitisHumanHuman poliovirusImmune responseImmunodeficient MouseIn VitroIncidenceInduction of ApoptosisInfectionInnate Immune ResponseInterferonsIntramuscular InjectionsKnowledgeLinkMethodsModelingMolecularMorbidity - disease rateMotor NeuronsMusMutationNatureNeuronsParalysedPathogenesisPathogenicityPatientsPatternPeripheralPharmacologic SubstancePoliomyelitisProteinsRecoveryResearch PersonnelRespiratory DiseaseRoleSensorySignal TransductionSliceSpinal CordSpinal cord injuryTestingTherapeuticTherapeutic InterventionTimeUnited StatesViralViral PathogenesisViral Structural ProteinsVirulence FactorsVirusVirus Diseasesacute flaccid myelitisage relatedantiviral drug developmentdisabilityemerging pathogenepidemiology studyexperienceexperimental studyhuman diseaseimprovedin vitro Modelin vivoinduced pluripotent stem cellinnovationjuvenile animalmembermortalitymouse modelneonatal infectionneonatal micenervous system disorderneurovirulencenovelpathogenic viruspreventprevious outbreakrespiratoryresponseretrograde transport
项目摘要
Virus infections of the central nervous system (CNS) are a significant cause of morbidity and mortality
worldwide. Proven treatments are limited to only a few viruses and even when treatments exist (e.g. acyclovir
for herpes simplex encephalitis) disability and death remain significant. Our knowledge of viral CNS infections,
particularly those involving the spinal cord, is limited and serves as a barrier against the development of novel
treatments for these devastating diseases. Enteroviruses are an important cause of virus-induced CNS
infections. Poliovirus is the most infamous member of the neurotrophic enteroviruses. However, several non-
polio human enteroviruses (NPEVs), including EV-D68, also target the CNS. NPEVs are common, causing an
estimated 10–15 million symptomatic annual infections in the US alone. Although most of these infections do
not result in CNS disease, these viruses can acquire the ability to be neuro-virulent. Recently, large outbreaks of
NPEVs have occurred worldwide that have been associated with neurologic disease and these viruses are
designated “re-emerging pathogens”. For example, in 2014, the United States experienced an epidemic of acute
flaccid myelitis (AFM) cases in children during a nationwide outbreak of previously rare enterovirus D68 (EV-
D68) respiratory disease. Approximately 50% of AFM patients had EV-D68 in respiratory secretions. However,
EV-D68 was not detected in the cerebrospinal fluid of any patient, preventing the establishment of a causative
link between EV-D68 and AFM. We have recently shown that many (including IL/52 and MO/47), but not all
(such as CA4231), clinical isolates of EV-D68 from the 2014 outbreak cause neurologic disease in neonatal mice
and propose to use this novel model of virus-induced CNS disease to define patterns and mechanisms of EV-
D68-induced paralysis. Using chimeric viruses we have demonstrated that the 5’ untranslated region (UTR)
and the viral structural proteins VP3 and VP1 are determinants of paralysis. In the proposed studies we will use
similar methods to determine which viral sequences are involved in specific mechanisms of paralysis, including
neuronal infectivity and apoptosis. An increased knowledge of pathogenic mechanisms that are involved in EV-
D68-induced CNS disease will inform the development of antivirals for EV-D68-induced AFM. In addition, by
focusing our efforts on host responses to EV-D68 infections our experiments may identify therapeutic
strategies that have broad spectrum applicability to additional EVs. Our studies may also have relevance for
other viral and non-viral causes of CNS disease.
中枢神经系统(CNS)的病毒感染是发病和死亡的重要原因
全世界。经证实的治疗方法仅限于少数病毒,即使存在治疗方法(例如阿昔洛韦)
单纯疱疹脑炎)残疾和死亡仍然很严重。我们对病毒性中枢神经系统感染的了解,
特别是那些涉及脊髓的,是有限的,并成为新的开发的障碍
治疗这些毁灭性的疾病。肠道病毒是病毒诱发中枢神经系统疾病的重要原因
感染。脊髓灰质炎病毒是神经营养性肠道病毒中最臭名昭著的成员。然而,一些非
脊髓灰质炎人类肠道病毒 (NPEV),包括 EV-D68,也以中枢神经系统为目标。 NPEV 很常见,导致
据估计,仅在美国每年就有 10-1500 万有症状的感染者。尽管大多数这些感染都
虽然不会导致中枢神经系统疾病,但这些病毒可以获得神经毒力的能力。近期,大面积爆发
NPEV 在世界范围内发生,与神经系统疾病相关,这些病毒
被指定为“重新出现的病原体”。例如,2014年,美国爆发了严重的新冠肺炎疫情。
此前罕见的肠道病毒 D68(EV-
D68) 呼吸道疾病。大约 50% 的 AFM 患者呼吸道分泌物中含有 EV-D68。然而,
在任何患者的脑脊液中均未检测到 EV-D68,从而防止了致病原因的建立
EV-D68 和 AFM 之间的链接。我们最近表明许多(包括 IL/52 和 MO/47),但不是全部
(如 CA4231),2014 年爆发的 EV-D68 临床分离株可导致新生小鼠出现神经系统疾病
并建议使用这种病毒诱导的中枢神经系统疾病的新模型来定义EV-的模式和机制
D68 引起的麻痹。使用嵌合病毒,我们已经证明 5' 非翻译区 (UTR)
病毒结构蛋白VP3和VP1是麻痹的决定因素。在拟议的研究中,我们将使用
确定哪些病毒序列参与特定麻痹机制的类似方法,包括
神经元感染和细胞凋亡。增加对 EV 致病机制的了解
D68 诱导的 CNS 疾病将为 EV-D68 诱导的 AFM 的抗病毒药物的开发提供信息。此外,通过
将我们的努力集中在宿主对 EV-D68 感染的反应上,我们的实验可能会确定治疗方法
对其他电动汽车具有广泛适用性的策略。我们的研究也可能与
中枢神经系统疾病的其他病毒和非病毒原因。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Kenneth L. Tyler其他文献
EV68-228-N monoclonal antibody treatment halts progression of paralysis in a mouse model of EV-D68 induced acute flaccid myelitis
EV68-228-N 单克隆抗体治疗可阻止 EV-D68 诱导的急性弛缓性脊髓炎小鼠模型中瘫痪的进展
- DOI:
10.1128/mbio.03906-24 - 发表时间:
2025-02-25 - 期刊:
- 影响因子:4.700
- 作者:
Michael J. Rudy;Courtney J. Wilson;Brendan Hinckley;Danielle C. Baker;Joshua M. Royal;Marshall P. Hoke;Miles B. Brennan;Matthew R. Vogt;Penny Clarke;Kenneth L. Tyler - 通讯作者:
Kenneth L. Tyler
Cerebral amyloid angiopathy with multiple intracerebral hemorrhages. Case report.
脑淀粉样血管病伴多发性脑出血。
- DOI:
10.3171/jns.1982.57.2.0286 - 发表时间:
1982 - 期刊:
- 影响因子:4.1
- 作者:
Kenneth L. Tyler;Charles E. Poletti;R. Heros - 通讯作者:
R. Heros
A rationally designed 2C inhibitor prevents enterovirus D68-infected mice from developing paralysis
合理设计的 2C 抑制剂可防止肠道病毒 D68 感染的小鼠出现瘫痪
- DOI:
10.1038/s41467-025-61083-8 - 发表时间:
2025-07-01 - 期刊:
- 影响因子:15.700
- 作者:
Kan Li;Michael J. Rudy;Yanmei Hu;Haozhou Tan;George Lambrinidis;Xiangmeng Wu;Kyriakos Georgiou;Bin Tan;Joshua Frost;Courtney Wilson;Penny Clarke;Antonios Kolocouris;Qing-yu Zhang;Kenneth L. Tyler;Jun Wang - 通讯作者:
Jun Wang
Case 45-1988
案例45-1988
- DOI:
10.1056/nejm198811103191908 - 发表时间:
1988 - 期刊:
- 影响因子:0
- 作者:
Kenneth L. Tyler;E. T. Hedley - 通讯作者:
E. T. Hedley
Usutu virus disease: a potential problem for North America?
乌苏图病毒病:北美潜在的问题?
- DOI:
10.1007/s13365-019-00818-y - 发表时间:
2019-12-19 - 期刊:
- 影响因子:1.900
- 作者:
Christine M. Gill;Ronak K. Kapadia;J. David Beckham;Amanda L. Piquet;Kenneth L. Tyler;Daniel M. Pastula - 通讯作者:
Daniel M. Pastula
Kenneth L. Tyler的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Kenneth L. Tyler', 18)}}的其他基金
EV-D68-induced CNS disease: pathogenic mechanisms and identification of therapeutic targets.
EV-D68诱导的中枢神经系统疾病:致病机制和治疗靶点的鉴定。
- 批准号:
10225583 - 财政年份:2018
- 资助金额:
$ 38.88万 - 项目类别:
EV-D68-induced CNS disease: pathogenic mechanisms and identification of therapeutic targets.
EV-D68诱导的中枢神经系统疾病:致病机制和治疗靶点的鉴定。
- 批准号:
9769165 - 财政年份:2018
- 资助金额:
$ 38.88万 - 项目类别:
EV-D68-induced CNS disease: pathogenic mechanisms and identification of therapeutic targets.
EV-D68诱导的中枢神经系统疾病:致病机制和治疗靶点的鉴定。
- 批准号:
9436831 - 财政年份:2017
- 资助金额:
$ 38.88万 - 项目类别:
Identification and evaluation of novel therapeutic targets for virus-induced neuronal disease
病毒引起的神经元疾病新治疗靶点的鉴定和评估
- 批准号:
8867128 - 财政年份:2012
- 资助金额:
$ 38.88万 - 项目类别:
Identification and evaluation of novel therapeutic targets for virus-induced neuronal disease
病毒引起的神经元疾病新治疗靶点的鉴定和评估
- 批准号:
8354615 - 财政年份:2012
- 资助金额:
$ 38.88万 - 项目类别:
Identification and evaluation of novel therapeutic targets for virus-induced neuronal disease
病毒引起的神经元疾病新治疗靶点的鉴定和评估
- 批准号:
8841447 - 财政年份:2012
- 资助金额:
$ 38.88万 - 项目类别:
Identification and evaluation of novel therapeutic targets for virus-induced neuronal disease
病毒引起的神经元疾病新治疗靶点的鉴定和评估
- 批准号:
8471054 - 财政年份:2012
- 资助金额:
$ 38.88万 - 项目类别:
Mechanisms of virus-induced injury in the brain and spinal cord
病毒引起的脑和脊髓损伤的机制
- 批准号:
8598010 - 财政年份:2011
- 资助金额:
$ 38.88万 - 项目类别:
Cellular genes and signaling pathways as therapeutic targets for virus-induced CN
细胞基因和信号通路作为病毒诱导 CN 的治疗靶点
- 批准号:
8215547 - 财政年份:2011
- 资助金额:
$ 38.88万 - 项目类别:
Role of Microglia in Protection Against West Nile Virus-induced CNS Injury: mechanisms and treatment strategies
小胶质细胞在预防西尼罗河病毒引起的中枢神经系统损伤中的作用:机制和治疗策略
- 批准号:
10513299 - 财政年份:2011
- 资助金额:
$ 38.88万 - 项目类别:
相似海外基金
Impact of alternative polyadenylation of 3'-untranslated regions in the PI3K/AKT cascade on microRNA
PI3K/AKT 级联中 3-非翻译区的替代多聚腺苷酸化对 microRNA 的影响
- 批准号:
573541-2022 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
University Undergraduate Student Research Awards
How do untranslated regions of cannabinoid receptor type 1 mRNA determine receptor subcellular localisation and function?
1 型大麻素受体 mRNA 的非翻译区如何决定受体亚细胞定位和功能?
- 批准号:
2744317 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
Studentship
MICA:Synthetic untranslated regions for direct delivery of therapeutic mRNAs
MICA:用于直接递送治疗性 mRNA 的合成非翻译区
- 批准号:
MR/V010948/1 - 财政年份:2021
- 资助金额:
$ 38.88万 - 项目类别:
Research Grant
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10019570 - 财政年份:2019
- 资助金额:
$ 38.88万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10223370 - 财政年份:2019
- 资助金额:
$ 38.88万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10455108 - 财政年份:2019
- 资助金额:
$ 38.88万 - 项目类别:
Synergistic microRNA-binding sites, and 3' untranslated regions: a dialogue of silence
协同的 microRNA 结合位点和 3 非翻译区:沉默的对话
- 批准号:
255762 - 财政年份:2012
- 资助金额:
$ 38.88万 - 项目类别:
Operating Grants
Analysis of long untranslated regions in Nipah virus genome
尼帕病毒基因组长非翻译区分析
- 批准号:
20790351 - 财政年份:2008
- 资助金额:
$ 38.88万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Search for mRNA elements involved in the compatibility between 5' untranslated regions and coding regions in chloroplast translation
寻找参与叶绿体翻译中 5 非翻译区和编码区之间兼容性的 mRNA 元件
- 批准号:
19370021 - 财政年份:2007
- 资助金额:
$ 38.88万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Post-transcriptional Regulation of PPAR-g Expression by 5'-Untranslated Regions
5-非翻译区对 PPAR-g 表达的转录后调控
- 批准号:
7131841 - 财政年份:2006
- 资助金额:
$ 38.88万 - 项目类别:














{{item.name}}会员




