Project 2
Project 2
批准号:
10199032
负责人:
THOMAS E SCAMMELL
金额:
$43.45万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-07-01 至 2025-06-30
关键词:
AddressAffectAfferent PathwaysAir MovementsAnatomyArousalAutomobile DrivingBrain StemCalcitonin Gene-Related PeptideCalciumContinuous Positive Airway PressureDrowsinessElectroencephalographyExposure toFiberFrequenciesGoalsHypercapniaHypothalamic structureImageIn Situ HybridizationIn VitroLateralMapsMeasuresMechanoreceptorsMethodsMusNeuronsObstructive Sleep ApneaPathway interactionsPatientsPatternPharmaceutical PreparationsPharmacologyPhotometryProsencephalonRecurrenceSignal PathwaySignal TransductionSleepSleep Apnea SyndromesSleep DeprivationSleep disturbancesSliceSynapsesTechniquesTidal VolumeTimeairway obstructionexperimental studyimprovedmethod developmentmultidisciplinaryneurochemistryneuromechanismparabrachial nucleuspreservationpreventreceptorreceptor expressionreceptor functionrespiratoryresponsesingle cell sequencingsingle-cell RNA sequencingtranslational impactventilation
中文摘要
项目摘要/摘要-项目2
在阻塞性睡眠呼吸暂停(OSA)患者中,气流阻塞会导致高碳酸血症和其他信号
这可以增加通气量,扩张呼吸道,还可以从睡眠中唤醒大脑皮层。目前的治疗方法包括
因为CPAP专注于呼吸道开放,但对这些治疗的依从性很差,许多患者继续
白天昏昏欲睡。因为反复从睡眠中唤醒会导致白天困倦和其他
OSA的后果,在不中断通风的情况下维持OSA睡眠的新方法将解决
这是阻塞性睡眠呼吸暂停综合症治疗中尚未得到满足的重要需求。
在P01的最后一个周期中,萨珀博士的团队(项目1)显示,降钙素基因相关肽
臂旁外侧核的降钙素基因相关肽(CGRP)神经元是皮层觉醒所必需的
高碳酸血症。具体地说,PBCGRP神经元的失活在很大程度上延迟或消除了大脑皮质的觉醒。
对高碳酸血症的反应而不会使呼吸反应迟钝。因此,PBCGRP神经元对
驱动皮质觉醒,但它们不是对高碳酸血症的呼吸系统反应所必需的。我们假设
激活PBCGRP神经元的抑制性输入将延迟或消除皮质对高碳酸血症的觉醒
而不会改变呼吸反应。
我们的目标是识别这些输入及其在PBCGRP神经元上的受体,最终目标是
选择性降低PBCGRP神经元的活性以防止皮质觉醒,同时保持通气性
回应。该项目与项目1、项目3和项目4很好地协同工作,这些项目旨在增强对
小鼠的高碳酸血症,以及旨在确定改善OSA的药理学方法的项目5
人民。我们将首先使用条件和常规追踪方法来识别PBCGRP的传入
神经元,然后我们将使用通道视紫红质辅助电路映射(CRACM)来建立突触
连通性。利用单细胞测序技术,我们将鉴定PBCGRP表达的受体
并用原位杂交和体外钙成像证实受体的表达。到时候我们会的
使用FOS和纤维光度法来确定PBCGRP神经元的哪些传入通路是睡眠活跃的。
最后,我们将确定通过抑制输入到PBCGRP神经元的信号是否延迟或消除
短暂的高碳酸血症引起的皮质觉醒。我们将测量大脑皮质觉醒后的潜伏期
高碳酸血症与光刺激对PBCGRP神经元的抑制输入相结合,然后
外周降钙素基因相关肽神经元的药物抑制。
总的来说,这些多学科实验将确定关键的解剖学和神经化学输入
应为阻塞性睡眠呼吸暂停综合征患者维持睡眠提供新的药理学机会的PBCGRP神经元
而不会抑制呼吸道的开放。
英文摘要
Project Summary/Abstract – Project 2
In people with obstructive sleep apnea (OSA), airflow obstruction results in hypercarbia and other signals
that increase ventilation, dilate the airway, and also trigger cortical arousals from sleep. Current therapies such
as CPAP focus on airway opening, but compliance with these therapies is poor, and many patients continue to
have daytime sleepiness. As recurrent arousals from sleep contribute to daytime sleepiness and other
consequences of OSA, new methods that maintain sleep in OSA without disrupting ventilation would address
an important, unmet need in OSA treatment.
In the last cycle of this P01, Dr. Saper’s group (Project 1) showed that calcitonin gene-related peptide
(CGRP) neurons of the lateral parabrachial nucleus are necessary for cortical arousals in response to
hypercapnia. Specifically, inactivation of PBCGRP neurons substantially delays or eliminates cortical arousals in
response to hypercapnia without blunting ventilatory responses. Thus, the PBCGRP neurons are essential for
driving cortical arousals, but they are not necessary for ventilatory responses to hypercapnia. We hypothesize
that activation of inhibitory inputs to the PBCGRP neurons will delay or eliminate cortical arousals to hypercapnia
without altering ventilatory responses.
Our Aims seek to identify these inputs and their receptors on the PBCGRP neurons, with the ultimate goal of
selectively reducing activity in the PBCGRP neurons to prevent cortical arousals while preserving ventilatory
responses. This Project synergizes well with Projects 1, 3, and 4 that seek to enhance ventilatory responses to
hypercapnia in mice, and Project 5 which seeks to identify pharmacological methods to improve OSA in
people. We will first use conditional and conventional tracing methods to identify afferents to the PBCGRP
neurons, and then we will use Channelrhodopsin-assisted circuit mapping (CRACM) to establish synaptic
connectivity. Using single cell sequencing techniques, we will then identify receptors expressed by the PBCGRP
neurons, and confirm receptor expression using in situ hybridization and in vitro calcium imaging. We will then
use fos and fiber photometry to determine which afferent pathways to the PBCGRP neurons are sleep-active.
Last, we will determine whether signaling through inhibitory inputs to the PBCGRP neurons delays or eliminates
cortical arousals triggered by brief period of hypercapnia. We will measure the latency to cortical arousal after
hypercapnia in combination with photostimulation of inhibitory inputs to the PBCGRP neurons and then with
pharmacological inhibition of the PBCGRP neurons.
Collectively, these multidisciplinary experiments will identify crucial anatomical and neurochemical inputs to
the PBCGRP neurons that should provide new pharmacological opportunities for maintaining sleep in OSA
without inhibiting airway opening.
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会议论文
Project 2
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批准号:10674876
-
项目类别:
-
资助金额:$43.46万
-
财政年份:2020
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Project 2
-
批准号:10491088
-
项目类别:
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资助金额:$43.46万
-
财政年份:2020
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Mechanisms of Cataplexy
-
批准号:10476056
-
项目类别:
-
资助金额:$4.71万
-
财政年份:2018
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Mechanisms of Cataplexy
-
批准号:9904788
-
项目类别:
-
资助金额:$38.28万
-
财政年份:2018
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Sleep disturbance as a risk factor for developing chronic pain
-
批准号:8368585
-
项目类别:
-
资助金额:$43.87万
-
财政年份:2012
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Sleep disturbance as a risk factor for developing chronic pain
-
批准号:8680211
-
项目类别:
-
资助金额:$41.76万
-
财政年份:2012
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Sleep disturbance as a risk factor for developing chronic pain
-
批准号:8517093
-
项目类别:
-
资助金额:$40.2万
-
财政年份:2012
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Wakefulness and Forebrain Activation by Orexin Neurons
-
批准号:8243531
-
项目类别:
-
资助金额:$46.27万
-
财政年份:2011
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Wakefulness and Forebrain Activation by Orexin Neurons
-
批准号:7798783
-
项目类别:
-
资助金额:$45.77万
-
财政年份:2010
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Project 2- Scammell
-
批准号:9096141
-
项目类别:
-
资助金额:$42.02万
-
财政年份:2010
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Project 2- Scammell
-
批准号:8794522
-
项目类别:
-
资助金额:$41.85万
-
财政年份:2010
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Identification Orexinergic Wake-Promoting Pathways
-
批准号:6716899
-
项目类别:
-
资助金额:$30.92万
-
财政年份:2003
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Circadian and Aminergic Regulation of Orexin Neurons
-
批准号:6937263
-
项目类别:
-
资助金额:$29.46万
-
财政年份:2001
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Circadian and Aminergic Regulation of Orexin Neurons
-
批准号:6383146
-
项目类别:
-
资助金额:$29.87万
-
财政年份:2001
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Circadian and Aminergic Regulation of Orexin Neurons
-
批准号:6646571
-
项目类别:
-
资助金额:$29.47万
-
财政年份:2001
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Circadian and Aminergic Regulation of Orexin Neurons
-
批准号:6835031
-
项目类别:
-
资助金额:$6.14万
-
财政年份:2001
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Circadian and Aminergic Regulation of Orexin Neurons
-
批准号:6528888
-
项目类别:
-
资助金额:$27.82万
-
财政年份:2001
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Circadian and Aminergic Regulation of Orexin Neurons
-
批准号:6785250
-
项目类别:
-
资助金额:$37.29万
-
财政年份:2001
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Orexin and the Control of Cataplexy
-
批准号:7266770
-
项目类别:
-
资助金额:$37.19万
-
财政年份:2000
-
负责人:THOMAS E SCAMMELL
-
依托单位:
Orexin and the Control of Cataplexy
-
批准号:7410106
-
项目类别:
-
资助金额:$37.19万
-
财政年份:2000
-
负责人:THOMAS E SCAMMELL
-
依托单位:
海外基金