Investigation of chromosomally integrated Human Herpesvirus 6 as a risk factor for Alzheimer's disease
染色体整合人类疱疹病毒 6 作为阿尔茨海默病危险因素的研究
基本信息
- 批准号:9904309
- 负责人:
- 金额:$ 20.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAlzheimer&aposs DiseaseAlzheimer&aposs disease diagnosisAlzheimer&aposs disease patientAlzheimer&aposs disease riskAmyloid beta-ProteinAntibodiesAntibody RepertoireAutopsyBiological MarkersBiologyCellsChromosomesClassificationClinicalCommunitiesDNADNA MarkersDNA SequenceDataData SetDementiaDevelopmentFluorescent in Situ HybridizationFutureGene ExpressionGeneticGenetic DiseasesGenetic RiskGoalsHHV-6AHHV-6BHerpesviridaeHuman Herpesvirus 6Human Herpesvirus 7Immunocompromised HostIndividualInheritedInvestigationLinkMedicalMicrobeMolecularNatural experimentNerve DegenerationNeuronsOutcomePathogenesisPatientsPopulationProcessRNA SequencesRegulationReportingResearchResearch PersonnelResolutionRisk FactorsRisk stratificationRoleRoseolovirusSenile PlaquesSjogren&aposs SyndromeSuggestionTimeValidationVariantViralViral PhysiologyViral ProteinsVirusaging brainantimicrobialbrain tissuecohortcomparativedensitydigitaldisorder subtypeendophenotypeexomegenetic associationimprovedinsightinterestmolecular diagnosticsmultiple omicsneuropathologynext generation sequencingnovelpathogenpathogenic bacteriapathogenic viruspatient subsetspre-clinicalrisk varianttraittranscriptome sequencingtranscriptomicstranslational studyviral RNAwhole genome
项目摘要
Project Summary
Important roles for microbes and antimicrobial defenses in the pathogenesis of Alzheimer's disease (AD) have
been postulated and investigated for at least six decades, beginning with Sjögren in 1952. The proliferation of
large, multiomic Alzheimer's disease (AD) focused data sets offer unprecedented and unbiased views of the
molecular networks that underlie AD. Through the direct examination of viral RNA and DNA sequences in next
generation sequencing data, we have observed the presence of many viral species in the aging brain, and linked
multiple viral species with AD biology, including regulation of AD genetic risk networks, AD gene expression
changes, and association with clinical dementia rating and neuropathology burden. Together, these findings
indicate that multiple viruses are at increased abundance in AD, across multiple brain tissues, with prominent
roles for Roseoloviruses HHV-6A, HHV-6B and HHV-7 (Readhead et al, In Press, Neuron).
A key challenge for the “pathogen hypothesis” of AD, is to understand whether such findings represent a
causal contribution, or reflect opportunistic passengers of a general neurodegenerative process. HHV-6A, HHV-
6B, and HHV-7 are remarkable among viruses for their capacity to integrate into subtelomeric regions of host
cell chromosomes, and recent studies have shown that inherited, chromosomally integrated HHV-6 (ciHHV-6) is
present in approximately 1% of the US and UK population. This offers the opportunity for a natural experiment,
where we can potentially link an inherited viral factor, with AD risk, and better address the plausibility of whether
viruses such as these, are capable of causally contributing to the onset and/or progression of AD, at least under
some circumstances. Our hypothesis is that iciHHV-6 will emerge as a risk factor for developing AD. This is a
valuable hypothesis to evaluate, as: (1) it represents an opportunity to identify a novel AD patient subpopulation,
which could inform subsequent translational studies, and (2) studying these viruses in an inherited form, will
enable us to better understand the plausibility of a causal role for viruses in AD.
Our preliminary studies of whole genome sequences (WGS) and whole exome sequences (WES)
generated on the individuals in the cohort described above, have shown some evidence of increased rates of
iciHHV-6 among individuals with AD, however the cohort size is only modestly powered to detect differences in
rare inherited variations like iciHHV-6. The goal of this proposed study, is to combine available genetic data from
the Alzheimer's Disease Sequencing Project and Accelerating Medical Partnerships in Alzheimer's disease to
identify instances of iciHHV-6 within this cohort, and perform a genetic association study that evaluates whether
iciHHV-6 is a risk factor for AD, or AD related traits.
项目摘要
微生物和抗微生物防御在阿尔茨海默病(AD)发病机制中的重要作用,
从1952年Sjögren开始,至少有60年的假设和研究。扩散
大型,多组阿尔茨海默病(AD)集中的数据集提供了前所未有的和公正的观点,
AD的分子网络。通过对病毒RNA和DNA序列的直接检测,
根据第二代测序数据,我们观察到许多病毒种类在衰老的大脑中存在,并与之相关。
多种病毒种属与AD生物学,包括AD遗传风险网络的调节,AD基因表达
变化,以及与临床痴呆评级和神经病理学负担的相关性。总之,这些发现
表明多种病毒在AD中的丰度增加,在多种脑组织中,
对于玫瑰花状病毒HHV-6A、HHV-6 B和HHV-7的作用(Readhead等,In Press,Neuron)。
AD的“病原体假说”的一个关键挑战是了解这些发现是否代表了AD的一个重要特征。
因果关系的贡献,或反映一般神经退行性过程的机会乘客。HHV-6A、HHV-
HHV-6 B和HHV-7在病毒中具有显著的整合到宿主的亚端粒区域的能力
细胞染色体,最近的研究表明,遗传的,染色体整合的HHV-6(ciHHV-6)是
目前在美国和英国人口的约1%。这为自然实验提供了机会,
我们可以潜在地将遗传性病毒因素与AD风险联系起来,并更好地解决
诸如这些的病毒能够至少在一定程度上导致AD的发作和/或进展。
一些情况。我们的假设是,iciHHV-6将成为发展AD的危险因素。这是一
值得评估的有价值的假设,因为:(1)它代表了识别新型AD患者亚群的机会,
这可以为后续的翻译研究提供信息,(2)以遗传形式研究这些病毒,
使我们能够更好地了解病毒在AD中因果作用的可能性。
我们对全基因组序列(WGS)和全外显子组序列(WES)进行了初步研究
在上述队列中的个体上产生的,已经显示出一些证据表明,
然而,队列规模仅具有适度的把握度来检测AD个体中的iciHHV-6的差异,
像iciHHV-6这样罕见的遗传变异这项研究的目的是将联合收割机的可用遗传数据,
阿尔茨海默病测序项目和加速阿尔茨海默病医疗合作,
确定该队列中的iciHHV-6实例,并进行遗传关联研究,评估是否
iciHHV-6是AD或AD相关性状的危险因素。
项目成果
期刊论文数量(0)
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Benjamin Readhead其他文献
Benjamin Readhead的其他文献
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{{ truncateString('Benjamin Readhead', 18)}}的其他基金
Identification of the genetic and transcriptomic networks of cognitive and neuropathological resilience to Alzheimer’s disease associated viruses
识别阿尔茨海默病相关病毒的认知和神经病理恢复力的遗传和转录组网络
- 批准号:
10076393 - 财政年份:2020
- 资助金额:
$ 20.66万 - 项目类别:
Identification of the genetic and transcriptomic networks of cognitive and neuropathological resilience to Alzheimer's disease associated viruses
识别阿尔茨海默病相关病毒的认知和神经病理恢复力的遗传和转录组网络
- 批准号:
9929397 - 财政年份:2018
- 资助金额:
$ 20.66万 - 项目类别:
Identification of the genetic and transcriptomic networks of cognitive and neuropathological resilience to AlzheimerâÂÂs disease associated viruses
识别阿尔茨海默氏病相关病毒的认知和神经病理恢复力的遗传和转录组网络
- 批准号:
10221574 - 财政年份:2018
- 资助金额:
$ 20.66万 - 项目类别:
Identification of the genetic and transcriptomic networks of cognitive and neuropathological resilience to AlzheimerâÂÂs disease associated viruses
识别阿尔茨海默氏病相关病毒的认知和神经病理恢复力的遗传和转录组网络
- 批准号:
10457833 - 财政年份:2018
- 资助金额:
$ 20.66万 - 项目类别:
Identification of the genetic and transcriptomic networks of cognitive and neuropathological resilience to Alzheimer’s disease associated viruses
识别阿尔茨海默病相关病毒的认知和神经病理恢复力的遗传和转录组网络
- 批准号:
10553862 - 财政年份:2018
- 资助金额:
$ 20.66万 - 项目类别: