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：
10446865
负责人：
MICHAEL G ROSENFELD
金额：
$ 41.65万
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/10446865
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 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 Herpesviridae Herpesvirus 1 Human Immune Impaired cognition Incidence Individual Infection 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 Research Retrotransposon Role SARS-CoV-2 spike protein Sampling Sentinel Small Nuclear RNA 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 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 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.

抽象的阿尔茨海默病 (AD) 提出了巨大的治疗挑战，因为目前的干预措施已经失败 GWAS 发现的大多数 AD 遗传风险变异存在于非基因组的编码区域，表明基因表达的改变有助于易感性现在多项报告表明，单纯疱疹病毒 1 (HSV1) 和其他微生物可以导致散发性 AD。累积在大脑中会增加AD/痴呆症的发病率，同时有证据表明其与重新激活有关。关于潜伏 HSV1 感染导致 AD 的研究，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 SARS-CoV-2 引起的 COVID-19 可能会包括神经系统和神经认知后遗症，可能会影响 AD 的发作或病程。通过采用强大的先进新基因组技术来表征细胞类型特异性的最新发现特定病毒基因产物的转录影响以及细胞自主与非细胞自主效应，包括 HSV1 潜伏 lncRNA 转录物和 SARS-CoV-2 刺突蛋白，它们会导致神经毒性使用改良的单核测序方法，可以实现散发性 AD 的特征。为了在同一个细胞核中同时评估 DNA 可及性和全局转录，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，最终可以识别作用于相关调节增强子的关键转录因子这将使我们能够阐明病毒是如何发挥作用的。基因产物改变各种神经元中与散发性 AD 相关的增强子景观和转录网络此外，我们将研究意义（S）和非神经元细胞类型和亚型的假设。反义 (AS) LAT 通过与宿主基因组中的特定调控元件相关联来影响转录我们进一步与共同调节因子 KAP1 合作影响多个 AD 易感位点的表达。 S-LAT 通过引起神经元功能障碍和炎症胶质细胞来影响 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会抑制人类内源性逆转录病毒 (HERV) 重复序列，而 AS-LAT 会调节这些重复序列通过促进抗炎基因表达谱来消除有害影响，并可以进一步减轻先天性通过直接抑制 AD 相关的前哨激酶来调节免疫反应以及细胞死亡程序总的来说，拟议的研究将以非基因组方式进行 PKR，从而产生关键的细胞类型特异性见解。散发性 AD 的病理轨迹可能受到多种传染性和非传染性因素的调节微生物对大脑的伤害。