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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
病毒 IncRNA 调节与散发性阿尔茨海默病相关的宿主基因组转录程序
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

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中文摘要
翻译
摘要 阿尔茨海默病(AD)提出了一个艰巨的治疗挑战,因为目前的干预措施已经失败 来减缓疾病的发展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,这表明基因表达的改变有助于易感性, 零星AD。现在有多份报告表明,单纯疱疹病毒1(HSV 1)和其他微生物可以 在大脑中积累,增加AD/痴呆的发病率。虽然有证据表明 潜伏性HSV 1感染对AD的影响,潜伏状态本身的病理潜力尚未得到解决。 此外,现在人们担心,由大流行性SARS-CoV-2引起的COVID-19可能 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 通过采用强大的新基因组技术来表征细胞类型特异性, 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HSV 1潜伏期lncRNA转录本和SARS-CoV-2刺突蛋白,它们有助于神经毒性, 具有偶发性AD特征的节目。使用改良的单核测序方法, 为了在同一个细胞核中同时评估DNA可及性和整体转录,我们将 继续我们对人类对照和AD大脑样本的询问,以揭示细胞类型特异性衰老与 散发性AD中每种CNS细胞类型的病理轨迹树,最终允许识别 关键的转录因子作用于相关的调节增强子。这将使我们能够阐明病毒如何 基因产物改变与散发性AD相关的增强子景观和转录网络, 以及非神经元细胞类型和亚型。此外,我们还将研究意义(S)和 反义(AS)LAT通过与宿主基因组中的特异性调控元件结合来影响转录, 与辅助调节因子KAP 1合作影响多个AD易感基因座的表达。我们进一步 假设S-LAT通过引起神经元功能障碍和炎性神经胶质细胞增生来影响AD过程。 至少部分通过下调编码KRAB锌指蛋白(KZFP)的基因簇来激活 通常抑制人类内源性逆转录病毒(HERV)重复序列,而AS-LAT调节这些重复序列。 通过促进抗炎基因表达谱来抑制有害作用,并且可以进一步减轻先天性 通过直接抑制AD相关的哨兵激酶, 非基因组方式的PKR。总的来说,拟议的研究将产生关键的细胞类型特异性的见解, 散发性AD的病理轨迹可能受到多种感染性和非感染性疾病的调节, 微生物对大脑的伤害
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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