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

项目成果

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会议论文数量(0)
专利数量(0)

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{{ 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:
    10199027
  • 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:
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:

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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:
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  • 批准号:
    8243530
  • 财政年份:
    2011
  • 资助金额:
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  • 批准号:
    8794517
  • 财政年份:
    2010
  • 资助金额:
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Mechanisms of Arousal in Sleep Apnea
睡眠呼吸暂停的唤醒机制
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睡眠呼吸暂停的唤醒机制
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  • 财政年份:
    2010
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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:
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  • 财政年份:
    2010
  • 资助金额:
    $ 43.46万
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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
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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:
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    $ 43.46万
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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
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