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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.

摘要