Viral IncRNAs Regulate Host Genomic Transcriptional Programs Associated with Sporadic Alzheimer's Disease
Viral IncRNAs Regulate Host Genomic Transcriptional Programs Associated with Sporadic Alzheimer's Disease
批准号:
10650398
负责人:
MICHAEL G ROSENFELD
金额:
$40.07万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-07-01 至 2027-06-30
关键词:
2019-nCoVAddressAffectAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease riskAmyloidAnti-Inflammatory AgentsAppearanceAstrocytesAttentionBindingBiological ModelsBrainCOVID-19COVID-19 pandemicCell DeathCell NucleusCellsCharacteristicsCollaborationsDNADataDementiaDepositionDisease ProgressionDisease susceptibilityDouble-Stranded RNADown-RegulationEctopic ExpressionEndogenous RetrovirusesEnhancersEtiologyEventFemaleFutureGene ClusterGene ExpressionGene Expression ProfileGene ProteinsGenesGeneticGenetic RiskGenetic TranscriptionGenetic VariationGenomeGenomicsGleanHerpes Simplex InfectionsHerpesvirus 1HumanImmuneImpaired cognitionIncidenceIndividualInflammatoryInnate Immune ResponseInterventionInvestigationLinkMicrobeMicrogliaMolecularMusNeurocognitiveNeurofibrillary TanglesNeurogliaNeurologicNeuronal DysfunctionNeuronsNucleic Acid Regulatory SequencesPathologicPathway interactionsPhosphotransferasesPredispositionProcessProteinsPublic HealthRegulationRegulatory ElementReportingRepressionResearchRetrotransposonRoleSARS-CoV-2 spike proteinSamplingSentinelSusceptibility GeneTechnologyTestingTherapeuticTherapeutic InterventionTranscriptTranscription AlterationTreesUnited StatesUntranslated RNAUp-RegulationViralViral GenomeViral ProteinsVirusVirus DiseasesZinc Fingersagedbiological specimen archivescell typeextracellulargene repressiongenome wide association studygenome-wide analysisglial activationinsightlatency associated transcriptlatent infectionmaleneuroinflammationneuron lossneuropathologyneurotoxicnon-genomicnovelnovel strategiesoutcome predictionprogramspromoterreactivation from latencyrecruitrisk variantsingle nucleus RNA-sequencingtranscription factor
中文摘要
摘要
阿尔茨海默病(AD)是一个巨大的治疗挑战,因为目前的干预措施已经失败
来延缓疾病的发展。Gwas鉴定的大多数AD遗传风险变异存在于非
基因组的编码区,这表明基因表达的变化有助于易感
零星的AD。现在有多份报告表明,单纯疱疹病毒1型(HSV1)和其他微生物可以
在大脑中积聚,增加AD/痴呆症的发病率。虽然有证据表明重新激活
关于潜伏的HSV1感染到AD,潜伏状态本身的病理潜力还没有被解决。
此外,现在有人担心,新冠肺炎是由SARS-CoV-2大流行引起的,可以
包括神经和神经认知后遗症,可能影响AD的发病或病程。在此,我们建议
通过使用强大的新基因组技术来表征特定类型的细胞,从而推动最新的发现
特定病毒基因产物的转录影响和细胞自主与非细胞自主效应,
包括HSV1潜伏的lncRNA转录本和SARS-CoV-2刺突蛋白,这些都有助于神经毒性
以零星AD为特征的节目。使用改进的单核测序方法,这允许
为了在同一个核中同时评估DNA可获得性和全球转录,我们将
继续我们对人类对照和AD大脑样本的询问,揭示特定细胞类型的衰老与
散发性AD中每种CNS细胞类型的病理轨迹树,最终允许识别
关键转录因子在涉及的调控增强子中起作用。这将使我们能够阐明病毒是如何
基因产物改变不同神经元中与散发性AD相关的增强子景观和转录网络
以及非神经细胞类型和亚型。此外,我们还将考察如下假设:感觉(S)和
反义(AS)LAT通过与宿主基因组中的特定调控元件结合来影响转录
与协调控子KAP1合作影响多个AD易感基因的表达。我们进一步
S-LAT通过导致神经元功能障碍和炎性胶质细胞影响AD过程的假说
至少部分地通过下调编码KRAB锌指蛋白(KZFP)的基因簇来激活
这通常会抑制人类内源性逆转录病毒(HERV)的重复,而AS-LAT会抑制这些
通过促进抗炎基因表达谱产生有害影响,并可进一步缓解先天
直接抑制AD相关的前哨蛋白激酶的免疫反应和细胞死亡程序
以非基因组方式表达的PKR。总的来说,拟议的研究将产生关键的特定细胞类型的见解
散发性阿尔茨海默病的病理轨迹可能受到不同感染性和非传染性疾病的影响
微生物对大脑的侮辱。
英文摘要
ABSTRACT
Alzheimer’s disease (AD) presents a formidable therapeutic challenge, as current interventions have failed
to slow disease progression. The majority of AD genetic risk variants identified by GWAS reside in non-
coding regions of the genome, suggesting that alterations in gene expression contribute to susceptibility for
sporadic AD. Multiple reports now suggest that Herpes Simplex Virus 1 (HSV1) and other microbes can
accumulate in the brain to increase the incidence of AD/dementia. While there is evidence linking reactivation
of latent HSV1 infection to AD, the pathological potential of the latent state per se has not been addressed.
Furthermore, there is now concern that COVID-19, which is caused by the pandemic SARS-CoV-2 and can
include neurological and neurocognitive sequelae, might impact the onset or course of AD. Here we propose to
advance recent findings by employing powerful new genomic technologies to characterize the cell type-specific
transcriptional impact and cell autonomous vs non-cell autonomous effects of specific viral gene products,
including HSV1 latency lncRNA transcripts and the SARS-CoV-2 Spike protein, that contribute to neurotoxic
programs characteristic of sporadic AD. Using a modified single-nucleus sequencing approach, which allows
for DNA accessibility and global transcription to be assessed simultaneously in the same nucleus, we will
continue our interrogation of human control and AD brain samples to reveal cell type-specific aging vs
pathological trajectory trees for each CNS cell type in sporadic AD, ultimately allowing for the identification of the
key transcription factors acting at implicated regulatory enhancers. This will enable us to elucidate how viral
gene products alter enhancer landscapes and transcriptional networks related to sporadic AD in various neuronal
and non-neuronal cell types and subtypes. In addition, we will investigate the hypothesis that the sense (S) and
antisense (AS) LATs impact transcription by associating with specific regulatory elements in the host genome in
collaboration with the co-regulator KAP1 to impact expression of multiple AD susceptibility loci. We further
hypothesize that the S-LAT influences the AD process by causing neuronal dysfunction and inflammatory glial
activation, at least in part, through down-regulation of gene clusters encoding KRAB zinc-finger proteins (KZFPs)
that normally repress human endogenous retrovirus (HERV) repeats, whereas the AS-LAT tempers these
deleterious effects by promoting an anti-inflammatory gene expression profile and can further mitigate the innate
immune response as well as cell death programs through direct inhibition of the AD-associated, sentinel kinase
PKR in a non-genomic fashion. Collectively, the proposed studies will yield crucial cell type-specific insights into
pathological trajectories in sporadic AD that may be subject to modulation by diverse infectious as well as non-
microbial insults to the brain.
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Viral IncRNAs Regulate Host Genomic Transcriptional Programs Associated with Sporadic Alzheimer's Disease
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