G-quadruplex DNA in senescence of the neurovascular unit

神经血管单元衰老中的 G-四链体 DNA

基本信息

项目摘要

Project Summary The neurovascular unit (NVU) is a functional structure that consists of endothelial cells, surrounded by an extracellular matrix, neurons, astrocytes, and pericytes. The NVU enables regulation of regional cerebral blood flow and nutrient delivery to the brain tissue. With aging, a structural weakening of the NVU occurs, which is also associated with inflammatory signaling and transport deficiencies. Critically, it is not clear how neurons, astrocytes, pericytes, and endothelial cells undergo senescence in the NVU, and whether there are differences in senescence pathways between healthy NVU aging and NVU in Alzheimer's diseases (AD). The G-quadruplex (G4) is a non-canonical DNA secondary structure formed by four DNA strands containing multiple runs of guanines. G4s play important roles in DNA recombination, replication, and regulation of transcription. In our data, we demonstrated that brain samples from aged mice contain more G4s than that of young mice. We showed that mice treated with a small-molecule G4 stabilizer develop cognitive impairment and accelerated brain aging. Using a heterochronic parabiosis mouse model, we also showed that the levels of G4s are decreased in the brain of old parabiont, compared to the age-matched iso-parabiotic mice, implicating presence of rejuvenating factors that can reverse the elevation of G4s with aging. The effect of the old parabiont on the young partner is more pronounced (more G4s in the young), suggesting a strong negative influence of aging factors. Importantly, in a mouse model of AD, we demonstrated that G4s are stabilized in the brains, well before the deposition of amyloid occurs. We hypothesize that these converging lines of evidence point at а mechanism of senescence. Thus, the primary objective of the proposed studies is to investigate G4-associated cellular senescence in the NVU, in aging and AD. In Aim 1, we will compare G4s across cell types in the NVU. In Aim 2, we will determine whether G4s preferentially accumulate in the NVUs of brain regions most vulnerable to neurodegeneration. In Aim 3, we will investigate how a peripheral factor, CXCL10, contributes to NVU's G4 senescence. G4s might be a novel pathway that can be targeted to mitigate the detrimental effects of cellular senescence in the brain.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Sean P Marrelli其他文献

Sean P Marrelli的其他文献

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{{ truncateString('Sean P Marrelli', 18)}}的其他基金

Modifying endothelial Piezo 1 function to improve brain perfusion in AD/ADRD
修改内皮 Piezo 1 功能以改善 AD/ADRD 患者的脑灌注
  • 批准号:
    10658645
  • 财政年份:
    2023
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    $ 156万
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Targeting intramural von Willebrand factor (VWF) to improve vasomotor function, enhance brain parenchymal clearance, & delay development of cerebral amyloid angiopathy (CAA) in conditions of amyloid
针对壁内血管性血友病因子 (VWF) 改善血管舒缩功能,增强脑实质清除,
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    10901009
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    2023
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    $ 156万
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SkyScan 1276: Multiscale Micro-CT SystemLaboratory
SkyScan 1276:多尺度微型 CT 系统实验室
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    10177395
  • 财政年份:
    2021
  • 资助金额:
    $ 156万
  • 项目类别:
Defining the role of endothelial Piezo1, a mechanosensitive ion channel, in providing resilience to vascular contributions to cognitive impairment and dementia (VCID)
定义内皮 Piezo1(一种机械敏感离子通道)在为认知障碍和痴呆 (VCID) 的血管提供恢复能力方面的作用
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    10419669
  • 财政年份:
    2021
  • 资助金额:
    $ 156万
  • 项目类别:
Multiple mechanisms of TRPV1-mediated brain protection following stroke
TRPV1介导的中风后脑保护的多种机制
  • 批准号:
    9236509
  • 财政年份:
    2017
  • 资助金额:
    $ 156万
  • 项目类别:
Multiple mechanisms of TRPV1-mediated brain protection following stroke
TRPV1介导的中风后脑保护的多种机制
  • 批准号:
    9551722
  • 财政年份:
    2017
  • 资助金额:
    $ 156万
  • 项目类别:
TRPV1-mediated induction of a protective heat shock response after stroke
TRPV1 介导的中风后保护性热休克反应的诱导
  • 批准号:
    8807397
  • 财政年份:
    2014
  • 资助金额:
    $ 156万
  • 项目类别:
TRPV1-mediated induction of a protective heat shock response after stroke
TRPV1 介导的中风后保护性热休克反应的诱导
  • 批准号:
    8919475
  • 财政年份:
    2014
  • 资助金额:
    $ 156万
  • 项目类别:
Targeting thermoreceptors for therapeutic hypothermia
靶向温度感受器进行低温治疗
  • 批准号:
    8327106
  • 财政年份:
    2011
  • 资助金额:
    $ 156万
  • 项目类别:
Targeting thermoreceptors for therapeutic hypothermia
靶向温度感受器进行低温治疗
  • 批准号:
    8233629
  • 财政年份:
    2011
  • 资助金额:
    $ 156万
  • 项目类别:

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