Project 1

项目1

基本信息

  • 批准号:
    10491085
  • 负责人:
  • 金额:
    $ 43.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

Summary/Abstract: Project 1 Patients with obstructive sleep apnea (OSA) may have hundreds of cycles over the night of loss of airway dilator motor tone and airway obstruction, followed by apnea, which is ended by an arousal, in which there is EEG desynchronization accompanied by return of airway dilator muscle tone, opening of the airway, and re- established ventilation. The EEG arousals cause sleep fragmentation and loss, resulting in cognitive impairment, and metabolic and cardiovascular consequences. We hypothesize that by augmenting brain circuits that keep the airway open while suppressing the EEG arousals, we can prevent these outcomes. We previously demonstrated that the EEG arousal to CO2 depends upon a population of CGRP neurons in the parabrachial nucleus (PBCGRP neurons). We now have identified a population of neurons expressing the transcription factor FoxP2 (PBFoxP2 neurons) which are just lateral to the PBCGRP neurons and which appear to be responsible for much of the increase in ventilation and in EMG tone of the genioglossus muscle (GG-EMG), an airway dilator, during CO2 exposure. In Specific Aim 1 we plan to use Channelrhodopsin2 to optogenetically activate PBFoxP2 neurons at baseline and during CO2 arousal, and will measure changes in respiratory rate, tidal volume, minute ventilation, and GG-EMG. We hypothesize that we can increase the respiratory response to CO2 in this way. We will then activate specific terminal fields of the PBFoxP2 neurons in the dorsal (nucleus of the solitary tract, hypoglossal nucleus) and ventral (preBötzinger complex, caudal ventrolateral medulla) to determine which of these contribute to the overall respiratory response. In Specific Aim 2 we will use ArchaerhodopsinT to inhibit the PBFoxP2 neurons or their terminal fields in the medulla, at baseline and during CO2 exposure, to see which are required for the respiratory response to CO2. Specific Aim 3 will use GCaMP6 calcium imaging to examine the responses of PBFoxP2 and PBCGRP neurons to CO2 arousal. We will examine this initially with fiber photometry, but then will record the responses of individual FoxP2 or CGRP neurons in the PB during CO2 arousal and other stimuli, to determine whether there are subsets within these groups that respond to specific classes of stimuli. Finally, in Specific Aim 4, we will use chemogenetics to enhance the firing of the PBFoxP2 neurons with the hM3Dq excitatory receptor and to suppress the firing of the PBCGRP neurons with the hGlyR inhibitory receptor. We plan then to combine these approaches in single animals to provide a proof of principle that selective and simultaneous activation of PBFoxP2 neurons and inhibition of PBCGRP neurons can allow a vigorous respiratory response, including increased GG-EMG in response to CO2 during sleep, without resulting in EEG arousal.
摘要/摘要:项目1 阻塞性睡眠呼吸暂停(OSA)患者可能有数百个周期的夜间气道丧失 扩张器运动张力和气道阻塞,然后是呼吸暂停,最后是觉醒,其中有 EEG去极化伴随气道扩张肌张力恢复、气道开放和再狭窄。 建立通风。EEG唤醒引起睡眠片段化和丧失,导致认知障碍。 以及代谢和心血管后果。我们假设通过增强大脑 保持气道开放同时抑制EEG唤醒的电路,我们可以防止这些结果。我们 先前证明,EEG对CO2的唤醒取决于大脑皮层中CGRP神经元的数量, 臂旁核(PBCGRP神经元)。我们现在已经确定了一群表达 转录因子FoxP 2(PBFoxP 2神经元),其位于PBCGRP神经元的侧面, 负责增加通气量和颏舌肌的EMG张力(GG-EMG), 呼吸道扩张器,在二氧化碳暴露期间。在具体目标1中,我们计划使用视紫红质2来 在基线和CO2唤醒期间,光遗传学激活PBFoxP 2神经元,并将测量 呼吸率、潮气量、每分钟通气量和GG-EMG。我们假设我们可以增加 对二氧化碳的呼吸反应。然后,我们将激活PBFoxP 2神经元的特定终末区域, 背侧(孤束核,舌下神经核)和腹侧(前Bötzinger复合体,尾侧 延髓腹外侧)以确定这些中的哪些对整体呼吸反应有贡献。在特定 目的2:利用古紫质T抑制延髓PBFoxP 2神经元或其终末野, 基线和CO2暴露期间,以了解对CO2的呼吸反应所需的条件。具体 目的3:应用GCaMP 6钙离子成像技术,观察PBFoxP 2和PBCGRP神经元对CO2的反应 兴奋我们将首先用纤维光度法对此进行检查,然后记录个体的反应。 在CO2唤醒和其他刺激过程中,PB中的FoxP 2或CGRP神经元,以确定是否有 这些群体中的子集对特定类别的刺激做出反应。最后,在具体目标4中,我们将使用 化学遗传学增强PBFoxP 2神经元与hM 3Dq兴奋性受体的放电, 用hGlyR抑制性受体抑制PBCGRP神经元的放电。然后我们计划将这些联合收割机 方法在单一的动物提供了一个原则的证明,选择性和同时激活的 PBFoxP 2神经元和PBCGRP神经元的抑制可以允许剧烈的呼吸反应,包括 在睡眠期间对CO2的反应增加了GG-EMG,而不会导致EEG唤醒。

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 }}

CLIFFORD B SAPER其他文献

CLIFFORD B SAPER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 }}

{{ truncateString('CLIFFORD B SAPER', 18)}}的其他基金

Project 1
项目1
  • 批准号:
    10674868
  • 财政年份:
    2020
  • 资助金额:
    $ 43.46万
  • 项目类别:
Mechanisms of sleep and sleep apnea
睡眠和睡眠呼吸暂停的机制
  • 批准号:
    10674855
  • 财政年份:
    2020
  • 资助金额:
    $ 43.46万
  • 项目类别:
Mechanisms of sleep and sleep apnea
睡眠和睡眠呼吸暂停的机制
  • 批准号:
    10491067
  • 财政年份:
    2020
  • 资助金额:
    $ 43.46万
  • 项目类别:
Mechanisms of sleep and sleep apnea
睡眠和睡眠呼吸暂停的机制
  • 批准号:
    10199026
  • 财政年份:
    2020
  • 资助金额:
    $ 43.46万
  • 项目类别:
Project 1
项目1
  • 批准号:
    10199031
  • 财政年份:
    2020
  • 资助金额:
    $ 43.46万
  • 项目类别:
Core A
核心A
  • 批准号:
    10674856
  • 财政年份:
    2020
  • 资助金额:
    $ 43.46万
  • 项目类别:
Core A
核心A
  • 批准号:
    10491080
  • 财政年份:
    2020
  • 资助金额:
    $ 43.46万
  • 项目类别:
Core A
核心A
  • 批准号:
    10199027
  • 财政年份:
    2020
  • 资助金额:
    $ 43.46万
  • 项目类别:
VTA VGluT2 Sociability Circuit in Genetic Autism
遗传性自闭症中的 VTA VGluT2 社交回路
  • 批准号:
    10091988
  • 财政年份:
    2018
  • 资助金额:
    $ 43.46万
  • 项目类别:
Neurobiology of Aggression Comorbidity in Autism
自闭症攻击性合并症的神经生物学
  • 批准号:
    10201418
  • 财政年份:
    2017
  • 资助金额:
    $ 43.46万
  • 项目类别:

相似海外基金

Upper airway collapsibility, loop gain and arousal threshold: an integrative therapeutic approach to obstructive sleep apnea
上气道塌陷、循环增益和唤醒阈值:阻塞性睡眠呼吸暂停的综合治疗方法
  • 批准号:
    10859275
  • 财政年份:
    2023
  • 资助金额:
    $ 43.46万
  • 项目类别:
Upper airway collapsibility, loop gain and arousal threshold: an integrative therapeutic approach to obstructive sleep apnea
上气道塌陷、循环增益和唤醒阈值:阻塞性睡眠呼吸暂停的综合治疗方法
  • 批准号:
    10516957
  • 财政年份:
    2022
  • 资助金额:
    $ 43.46万
  • 项目类别:
Arousal Threshold in the Pathogenesis of Obstructive Sleep Apnea
阻塞性睡眠呼吸暂停发病机制中的唤醒阈值
  • 批准号:
    8243530
  • 财政年份:
    2011
  • 资助金额:
    $ 43.46万
  • 项目类别:
Mechanisms of Arousal in Sleep Apnea
睡眠呼吸暂停的唤醒机制
  • 批准号:
    8794517
  • 财政年份:
    2010
  • 资助金额:
    $ 43.46万
  • 项目类别:
Mechanisms of Arousal in Sleep Apnea
睡眠呼吸暂停的唤醒机制
  • 批准号:
    9304291
  • 财政年份:
    2010
  • 资助金额:
    $ 43.46万
  • 项目类别:
Mechanisms of Arousal in Sleep Apnea
睡眠呼吸暂停的唤醒机制
  • 批准号:
    9096133
  • 财政年份:
    2010
  • 资助金额:
    $ 43.46万
  • 项目类别:
Arousal Threshold in the Pathogenesis of Obstructive Sleep Apnea
阻塞性睡眠呼吸暂停发病机制中的唤醒阈值
  • 批准号:
    7798778
  • 财政年份:
    2010
  • 资助金额:
    $ 43.46万
  • 项目类别:
The role of arousal in the pathogenesis of obstructive sleep apnea and implications for novel therapeutic treatments
觉醒在阻塞性睡眠呼吸暂停发病机制中的作用及其对新型治疗方法的影响
  • 批准号:
    nhmrc : 510392
  • 财政年份:
    2008
  • 资助金额:
    $ 43.46万
  • 项目类别:
    Early Career Fellowships
Arousal Threshold in the Pathogenesis of Obstructive Sleep Apnea
阻塞性睡眠呼吸暂停发病机制中的唤醒阈值
  • 批准号:
    8435427
  • 财政年份:
  • 资助金额:
    $ 43.46万
  • 项目类别:
Arousal Threshold in the Pathogenesis of Obstructive Sleep Apnea
阻塞性睡眠呼吸暂停发病机制中的唤醒阈值
  • 批准号:
    8377816
  • 财政年份:
  • 资助金额:
    $ 43.46万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了