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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

抽象的阿尔茨海默氏病（AD）提出了巨大的治疗挑战，因为目前的干预措施失败了减慢疾病进展。 GWA鉴定出的大多数AD遗传风险变异都存在于非 - 基因组的编码区域，表明基因表达的改变有助于对零星广告。现在的多个报告表明，单纯疱疹病毒1（HSV1）和其他微生物可以积聚在大脑中以增加AD/痴呆的事件。虽然有证据表明重新激活潜在的HSV1感染AD，潜在状态本身的病理潜力尚未得到解决。此外，现在担心Covid-19，这是由大流行SARS-COV-2引起的，可以包括神经学和神经认知后遗症，可能会影响AD的发作或过程。在这里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转录影响和细胞自主与特定病毒基因产物的非细胞自主效应，包括HSV1潜伏期LNCRNA转录本和SARS-COV-2尖峰蛋白，这有助于神经毒性零星广告的特征的程序。使用修改的单核测序方法，该方法允许为了简单地在同一核中评估DNA的可及性和全局转录，我们将继续我们对人类控制和AD脑样品的询问，以揭示细胞类型特异性衰老与零星AD中每种CNS细胞类型的病理轨迹树，最终允许鉴定作用于隐含调节增强剂的关键转录因子。这将使我们能够阐明病毒基因产品改变了与零星AD相关的各种神经元中的增强剂景观和转录网络和非神经元细胞类型和亚型。此外，我们将研究以下假设。反义（AS）LATS通过与宿主基因组中的特定调节元件相关联影响转录与共同调节器KAP1的合作，以影响多个AD易感性位置的表达。我们进一步假设S-LAT通过引起神经元功能障碍和炎症神经胶质来影响AD过程至少部分通过编码KRAB锌指蛋白（KZFPS）的基因簇的下调，至少部分通过下调通常会抑制人内源性逆转录病毒（HERV）重复通过促进抗炎基因表达谱并可以进一步减轻先天性来通过有害影响免疫反应以及通过直接抑制AD相关的前哨激酶来的细胞死亡程序 PKR以非基因组方式。总的来说，拟议的研究将产生至关重要的细胞类型特异性见解零星广告中的病理轨迹可能受到潜水员感染和非 - 微生物侮辱大脑。