Administrative Supplements to Existing NIH Grants and Cooperative Agreements

对现有 NIH 拨款和合作协议的行政补充

基本信息

  • 批准号:
    9929915
  • 负责人:
  • 金额:
    $ 32.97万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-05-15 至 2021-04-30
  • 项目状态:
    已结题

项目摘要

Project Summary: Substantial brain blood flow reductions are observed in Alzheimer’s disease (AD) patients and likely contribute to the cognitive symptoms of the disease. Recent work using in vivo multiphoton imaging has shown that neutrophil adhesion in brain capillaries is a cellular mechanism that causes reduced brain blood flow in AD mouse models, and has further shown that cognitive function is rapidly improved when neutrophil adhesion is blocked to increase brain blood flow. These results suggest that improved understanding of the nature and molecular causes of the vascular inflammation in the AD brain could suggest novel therapeutic strategies, complementary to anti-Amyloid and other treatment approaches currently in development, that aim to improve brain blood flow and potentially reduce cognitive symptoms of AD. In this request for supplemental funding, the aim is to pursue two important extensions of the existing grant. The first goal is to assess the impact of the clean environment the mouse models live in. The effect that underlies the decreased brain blood flow in AD mice is subtle — about 2% of brain capillaries are not flowing due to an adhered neutrophil. Several studies have shown that immune and inflammatory cell behavior in laboratory mice is altered when those mice are exposed to the flora of wild mice. AD and wild-type mice will be exposed to the flora of mice from pet shops, with controls kept in standard laboratory housing conditions. The incidence and cause of capillary stalling and the impact of capillary stalls on brain blood flow will be compared between these groups to determine if altered inflammatory cell phenotypes due to the clean environment of laboratory mice influences the capillary stalling phenomena that underlies brain blood flow deficits in AD mice. This work extends Aim 1 of the original proposal, which seeks to characterize the incidence and cause of non-flowing capillaries in AD mice. The second goal relates to increasing our understanding of the vascular inflammation that leads to increased neutrophil adhesion in capillaries in the AD mice. Recent work has shown that inhibition of NOX2-containing NAPDH oxidase, a reactive oxygen producing enzyme, decreases the incidence of capillary stalling in AD mice. Here, the proposal is to extract brain endothelial cells from AD and wild-type mice with and without inhibition of NAPDH oxidase, and use RNA sequencing to determine differences in gene expression between these four groups. Newly developed approaches that do not overly activate the endothelial cells during extraction and processing will be utilized. Such work to clarify the details of the inflammatory response is critically important for identifying a potential drug target to block this effect and improve brain blood flow in patients. Long term, systemic inhibition of neutrophil adhesion could have hard to manage side effects, and this gene expression data will help to identify a place to intervene that is more brain endothelia and AD specific. This work extends Aim 2 of the original proposal, which aims to identify the molecular signaling that leads to increased capillary stalling in AD mice.
项目摘要:在阿尔茨海默氏病(AD)患者中观察到大量脑血流量减少 并可能导致该疾病的认知症状。最近使用体内多光子成像的工作 已经表明,脑毛细血管中的嗜中性粒细胞粘合剂是导致脑部减少的细胞机制 AD小鼠模型中的血流,并进一步表明,当认知功能迅速提高 中性粒细胞粘附被阻断以增加脑血流。这些结果表明改善了 了解广告大脑中血管炎症的性质和分子原因可能表明 新型的热策略,抗淀粉样蛋白和其他治疗方法目前 发展,旨在改善脑血流并有可能减少AD的认知症状。在这个 要求补充资金的要求,目的是追求现有赠款的两个重要扩展。 第一个目标是评估鼠标模型所生活的清洁环境的影响。 AD小鼠的脑血流改善很微妙 - 大约2%的脑毛细血管不流动 粘附的中性粒细胞。几项研究表明,实验室的免疫和炎症细胞行为 当这些小鼠暴露于野生小鼠的菌群时,小鼠会改变。 AD和野生型小鼠将暴露 到宠物店的小鼠植物群,并在标准实验室住房条件下保存了控件。事件 将比较毛细管失速的原因以及毛细管摊位对脑血流的影响 这些组以确定由于实验室清洁环境而导致的炎症细胞表型是否改变 小鼠会影响脑血流定义的毛细管失速现象。这项工作 扩展了原始提案的目标1,该提议旨在表征事件和原因不流动的原因 AD小鼠的毛细血管。第二个目标与我们对血管炎症的理解有关 这导致AD小鼠毛细血管中的中性粒细胞广告增加。最近的工作表明 抑制含有NOX2的NAPDH氧化物,一种产生的活性氧,可降低 AD小鼠毛细管失速的发生率。在这里,建议是从AD中提取脑内皮细胞, 野生型小鼠有和不抑制NAPDH氧化物,并使用RNA测序确定 这四组之间的基因表达差异。新开发的方法不会过分 将利用在提取和加工过程中激活内皮细胞。这样的工作以澄清细节 炎症反应的重要性对于确定潜在的药物靶标至关重要 并改善患者的脑血流。长期,系统性抑制中性粒细胞粘附可能具有 难以管理副作用,此基因表达数据将有助于确定干预的地方 更多的大脑内皮和广告特定。这项工作扩展了原始提案的目标2,旨在 确定导致AD小鼠毛细管停滞增加的分子信号传导。

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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CHRIS B SCHAFFER其他文献

CHRIS B SCHAFFER的其他文献

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{{ truncateString('CHRIS B SCHAFFER', 18)}}的其他基金

Metabolic and neural activity normalization by cerebral blood flow increase in AD/ADRD models
AD/ADRD 模型中脑血流量增加使代谢和神经活动正常化
  • 批准号:
    10657935
  • 财政年份:
    2023
  • 资助金额:
    $ 32.97万
  • 项目类别:
STALLED CAPILLARY FLOW: A NOVEL MECHANISM FOR HYPOPERFUSION IN ALZHEIMER DISEASE
毛细血管血流停滞:阿尔茨海默病低灌注的一种新机制
  • 批准号:
    9756240
  • 财政年份:
    2015
  • 资助金额:
    $ 32.97万
  • 项目类别:
STALLED CAPILLARY FLOW: A NOVEL MECHANISM FOR HYPOPERFUSION IN ALZHEIMER DISEASE
毛细血管血流停滞:阿尔茨海默病低灌注的一种新机制
  • 批准号:
    8863677
  • 财政年份:
    2015
  • 资助金额:
    $ 32.97万
  • 项目类别:
Reducing morbidity in surgical resections: Third-harmonic generation microscopy a
降低手术切除的发病率:三次谐波发生显微镜a
  • 批准号:
    8720770
  • 财政年份:
    2013
  • 资助金额:
    $ 32.97万
  • 项目类别:
Chronic imaging of cellular dynamics after cortical microhemorrhage
皮质微出血后细胞动力学的慢性成像
  • 批准号:
    8719850
  • 财政年份:
    2013
  • 资助金额:
    $ 32.97万
  • 项目类别:
Reducing morbidity in surgical resections: Third-harmonic generation microscopy a
降低手术切除的发病率:三次谐波发生显微镜a
  • 批准号:
    8568862
  • 财政年份:
    2013
  • 资助金额:
    $ 32.97万
  • 项目类别:
Chronic imaging of cellular dynamics after cortical microhemorrhage
皮质微出血后细胞动力学的慢性成像
  • 批准号:
    8579569
  • 财政年份:
    2013
  • 资助金额:
    $ 32.97万
  • 项目类别:
Femtosecond laser-produced sub-surface cuts to halt focal epileptic seizures
飞秒激光产生的表面下切割可阻止局灶性癫痫发作
  • 批准号:
    8551771
  • 财政年份:
    2012
  • 资助金额:
    $ 32.97万
  • 项目类别:
Femtosecond laser-produced sub-surface cuts to halt focal epileptic seizures
飞秒激光产生的表面下切割可阻止局灶性癫痫发作
  • 批准号:
    8445824
  • 财政年份:
    2012
  • 资助金额:
    $ 32.97万
  • 项目类别:
Role of Cortical Microvascular Lesions in Amyloid-Beta Accumulation
皮质微血管病变在β-淀粉样蛋白积累中的作用
  • 批准号:
    7826969
  • 财政年份:
    2009
  • 资助金额:
    $ 32.97万
  • 项目类别:

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Multi-modality optical imaging of single-cell dynamics using supercontinuum light source
使用超连续谱光源的单细胞动力学多模态光学成像
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病毒引发的哮喘中 ECM 和白细胞粘附的上皮调节
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哮喘中上皮细胞对先天免疫反应的调节
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