Changes in Water Channel Localization to Astrocytic Endfeet with Aging

星形胶质细胞末足水道定位随衰老的变化

基本信息

  • 批准号:
    9395774
  • 负责人:
  • 金额:
    $ 4.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-01 至 2020-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary Alzheimer's disease (AD) is an age-linked neurodegenerative disease that is the leading cause of dementia and 6th leading cause of death in the United States. It is characterized pathologically by the accumulation of amyloid β (Aβ) peptides. In the healthy brain, several mechanisms facilitate clearance of Aβ prior to pathogenic accumulation. The function of these clearance mechanisms deteriorates as an individual ages. To develop effective therapeutic strategies for patients with AD, it is important to understand the mechanisms that drive Aβ clearance, and the source of their dysfunction in the aged brain. Previous research has shown that the recently described glymphatic system is one such mechanism involved in Aβ clearance that also demonstrates age-linked dysfunction. Proper glymphatic function relies on mixing of cerebrospinal spinal fluid (CSF) with interstitial fluid (ISF) along perivascular spaces throughout the brain. This process is mediated by water flux across astrocytes that ensheathe the brain vasculature. The water channel aquaporin-4 (AQP4) supports this water flux, and is highly localized to perivascular astrocytic endfeet in the healthy brain, but loses this localization in the aging brain and with AD status. Recent research has shown that in a transgenic mouse model of AD, deletion of the Aqp4 gene in mice increases Aβ plaque accumulation and worsens cognitive impairment. In aging mice and humans with AD, while overall expression of AQP4 is maintained, perivascular AQP4 localization is lost. Importantly, whether the loss of endfoot localization of AQP4 seen in the aging brain promotes accumulation of Aβ in a similar manner to that seen in Aqp4 knockout mice is not known. The goal of this proposal is to determine the role that loss of perivascular AQP4 localization plays in Aβ accumulation, and identify cellular mechanisms that contribute to the regulation of AQP4 perivascular localization and break down in the aging brain. In Aim 1, I will assess the effect of loss of perivascular localization on Aβ clearance using a mouse model that features both a lack of perivascular AQP4 localization and spontaneous Aβ plaque formation. In Aim 2 of the proposal I will investigate whether changes in dystrophin associated complex proteins regulate perivascular AQP4 localization in the aging brain, and how loss of their expression impacts Aβ plaque burden. In Aim 3 I will investigate a second candidate regulatory mechanism for AQP4 localization, the expression of alternate AQP4 isoforms using an astrocyte-specific viral overexpression paradigm to isolate the role of each AQP4 isoform. This study will be the first to define the consequences of age-linked loss of astrocytic perivascular AQP4 localization. Additionally it will be one of the first to examine the mechanisms underlying changes in perivascular AQP4 localization in vivo. The results of this study will provide insight into AQP4 as a potential therapeutic target for AD and other neuropathologies that demonstrate an accumulation of protein aggregates including Parkinson's and Huntington's disease.
项目摘要 阿尔茨海默病(AD)是一种与年龄相关的神经退行性疾病,是痴呆的主要原因,也是第六大 美国的死因。其病理特征是淀粉样β(Aβ)肽的积聚。在 在健康的大脑中,有几种机制促进Aβ在致病性积聚之前的清除。这些功能 清除机制随着个人年龄的增长而恶化。为AD患者制定有效的治疗策略, 了解老年人Aβ清除的机制及其功能障碍的来源很重要 个脑袋 先前的研究表明,最近描述的胶质淋巴系统是参与Aβ的机制之一 清除率也显示出与年龄相关的功能障碍。正常的胶质淋巴功能依赖于脑脊液和 脊髓液(CSF)与间质液(ISF)沿整个脑的血管周围空间沿着。这一过程是由 穿过包裹脑血管的星形胶质细胞的水流量。水通道水通道蛋白4(AQP4)支持这一点。 水通量,并高度定位于血管周围的星形胶质细胞终足在健康的大脑,但失去了这种定位在 大脑老化和AD状态。最近的研究表明,在AD的转基因小鼠模型中,Aqp4基因的缺失 小鼠中的基因增加了Aβ斑块的积累和阿尔茨海默氏症的认知障碍。在老年小鼠和AD患者中, 虽然AQP4的总体表达得以维持,但血管周围AQP4定位丧失。重要的是, 在衰老大脑中观察到的AQP4的末端定位促进Aβ的积累,其方式与在衰老大脑中观察到的相似。 Aqp4基因敲除小鼠是未知的。 本研究的目的是确定血管周围AQP4定位缺失在Aβ蓄积中的作用, 并确定有助于调节AQP4血管周围定位的细胞机制, 老化的大脑在目标1中,我将使用小鼠模型评估血管周围定位丧失对Aβ清除的影响 其特征在于缺乏血管周围AQP4定位和自发性Aβ斑块形成。在目标2中, 我将研究抗肌萎缩蛋白相关复合物蛋白的变化是否调节血管周围AQP4 在衰老大脑中的定位,以及它们的表达丧失如何影响Aβ斑块负荷。在目标3中,我将研究 AQP4定位的第二种候选调节机制,使用一种或多种细胞因子表达替代AQP4同种型。 星形胶质细胞特异性病毒过表达范例,以分离每种AQP4亚型的作用。 这项研究将是第一个定义与年龄相关的星形胶质细胞血管周围AQP4定位丢失的后果。 此外,它将是第一个研究血管周围AQP4定位变化的机制之一。 in vivo.这项研究的结果将提供对AQP4作为AD和其他疾病的潜在治疗靶点的深入了解。 表现出蛋白质聚集体积累的神经病理学,包括帕金森病和亨廷顿病。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Matthew Simon其他文献

Matthew Simon的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 4.4万
  • 项目类别:
    Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 4.4万
  • 项目类别:
    Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 4.4万
  • 项目类别:
    Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 4.4万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 4.4万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 4.4万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 4.4万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 4.4万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 4.4万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 4.4万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了