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: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650398
• 关键词: 2019-nCoV; Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Anti-Inflammatory Agents; Appearance; Astrocytes; Attention; Binding; Biological Models; Brain; COVID-19; COVID-19 pandemic; Cell Death; Cell Nucleus; Cells; Characteristics; Collaborations; DNA; Data; Dementia; Deposition; Disease Progression; Disease susceptibility; Double-Stranded RNA; Down-Regulation; Ectopic Expression; Endogenous Retroviruses; Enhancers; Etiology; Event; Female; Future; Gene Cluster; Gene Expression; Gene Expression Profile; Gene Proteins; Genes; Genetic; Genetic Risk; Genetic Transcription; Genetic Variation; Genome; Genomics; Glean; Herpes Simplex Infections; Herpesvirus 1; Human; Immune; Impaired cognition; Incidence; Individual; Inflammatory; Innate Immune Response; Intervention; Investigation; Link; Microbe; Microglia; Molecular; Mus; Neurocognitive; Neurofibrillary Tangles; Neuroglia; Neurologic; Neuronal Dysfunction; Neurons; Nucleic Acid Regulatory Sequences; Pathologic; Pathway interactions; Phosphotransferases; Predisposition; Process; Proteins; Public Health; Regulation; Regulatory Element; Reporting; Repression; Research; Retrotransposon; Role; SARS-CoV-2 spike protein; Sampling; Sentinel; Susceptibility Gene; Technology; Testing; Therapeutic; Therapeutic Intervention; Transcript; Transcription Alteration; Trees; United States; Untranslated RNA; Up-Regulation; Viral; Viral Genome; Viral Proteins; Virus; Virus Diseases; Zinc Fingers; aged; biological specimen archives; cell type; extracellular; gene repression; genome wide association study; genome-wide analysis; glial activation; insight; latency associated transcript; latent infection; male; neuroinflammation; neuron loss; neuropathology; neurotoxic; non-genomic; novel; novel strategies; outcome prediction; programs; promoter; reactivation from latency; recruit; risk variant; single nucleus RNA-sequencing; transcription factor

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.

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。