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

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

项目成果

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MICHAEL G ROSENFELD其他文献

MICHAEL G ROSENFELD的其他文献

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{{ truncateString('MICHAEL G ROSENFELD', 18)}}的其他基金

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:
    10446865
  • 财政年份:
    2022
  • 资助金额:
    $ 40.07万
  • 项目类别:
Revealing the roles of HSV1 lytic and latent transcripts in AD pathogenesis and therapy
揭示 HSV1 裂解转录物和潜伏转录物在 AD 发病机制和治疗中的作用
  • 批准号:
    10621810
  • 财政年份:
    2021
  • 资助金额:
    $ 40.07万
  • 项目类别:
Regulatory Landscape of the Aging Human Ovary
人类卵巢衰老的调控景观
  • 批准号:
    10441547
  • 财政年份:
    2020
  • 资助金额:
    $ 40.07万
  • 项目类别:
Regulatory Landscape of the Aging Human Ovary
人类卵巢衰老的调控景观
  • 批准号:
    10646190
  • 财政年份:
    2020
  • 资助金额:
    $ 40.07万
  • 项目类别:
Regulatory Landscape of the Aging Human Ovary
人类卵巢衰老的调控景观
  • 批准号:
    10264170
  • 财政年份:
    2020
  • 资助金额:
    $ 40.07万
  • 项目类别:
Regulatory Landscape of the Aging Human Ovary
人类卵巢衰老的调控景观
  • 批准号:
    10091772
  • 财政年份:
    2020
  • 资助金额:
    $ 40.07万
  • 项目类别:
A stress-induced promoter pause release program in cardiomyocytes protecting against myocardial infarction
心肌细胞中应激诱导的启动子暂停释放程序可预防心肌梗死
  • 批准号:
    10521252
  • 财政年份:
    2019
  • 资助金额:
    $ 40.07万
  • 项目类别:
Combinatorial regulation of the enhancer codes in senescence
衰老过程中增强子密码的组合调控
  • 批准号:
    10152492
  • 财政年份:
    2019
  • 资助金额:
    $ 40.07万
  • 项目类别:
A stress-induced promoter pause release program in cardiomyocytes protecting against myocardial infarction
心肌细胞中应激诱导的启动子暂停释放程序可预防心肌梗死
  • 批准号:
    10318093
  • 财政年份:
    2019
  • 资助金额:
    $ 40.07万
  • 项目类别:
Combinatorial regulation of the enhancer codes in senescence
衰老过程中增强子密码的组合调控
  • 批准号:
    10017129
  • 财政年份:
    2019
  • 资助金额:
    $ 40.07万
  • 项目类别:

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