Administrative Supplement to Serotonergic circuit mechanisms in postictal recovery and arousal
发作后恢复和唤醒过程中血清素回路机制的行政补充
基本信息
- 批准号:10841319
- 负责人:
- 金额:$ 2.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdministrative SupplementAnimal ModelAnimalsApneaArousalBiological MarkersCarbon DioxideCardiacCause of DeathCell NucleusCessation of lifeConfusionConsciousDataDeath RateDetectionDiseaseElectrocardiogramElectroencephalographyEpilepsyEtiologyFiberGeneticGoalsImpairmentIndividualInterventionIntractable EpilepsyLifeLinkMeasurableMeasurementMeasuresMethodsModelingMorbidity - disease rateMusNeuronsOutcomePathway interactionsPatientsPhenotypePhotometryPilocarpinePublic HealthPublishingRecoveryRegulationResearchRiskRisk MarkerRoleSeizuresSerotoninSleepStatus EpilepticusStimulusStrokeStuporSudden DeathSudden infant death syndromeSymptomsSystemTemporal Lobe EpilepsyTestingTherapeuticWakefulnessWorkchemical reductiondorsal raphe nucleusdravet syndromeepileptic encephalopathiesexperimental studyinsightmortalitymouse modelnervous system disordernoveloptogeneticsparabrachial nucleuspreventpreventive interventionprophylacticrespiratoryresponserisk stratificationsocietal costssudden unexpected death in epilepsy
项目摘要
ABSTRACT
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory
epilepsy. SUDEP is second only to stroke in years of potential life lost to neurological disease and is a
major public health problem. Several etiologies have been proposed for SUDEP including cardiac and
respiratory dysregulation. Another that is postulated is impaired arousal. Seizures impair arousal. Among
arousal stimuli, one that may be particularly relevant to SUDEP is CO2. CO2 rises following seizures and
is part of the seizure cessation mechanism. Seizures are frequently associated with ictal and post-ictal
central and obstructive apneas. Apnea further exacerbates the accumulation of CO2. Impairment of CO2-
arousal is proposed as an etiological factor in another sudden death entity, sudden infant death
syndrome, which has many parallels with SUDEP. We discovered that seizures impaired CO2-arousal in
seizure naïve mice and those that do not have a particularly profound death rate. Whether this is true in
mouse models with strong SUDEP phenotypes is unknown. Thus, our goal in this proposal is to determine
how seizures in different sleep states impair CO2-arousal in mouse models of temporal lobe epilepsy
(TLE) and the genetic epileptic encephalopathy, Dravet Syndrome (DS). In Aim 1 we will determine the
extent to which CO2-arousal is impaired in epilepsy models. We will focus on the pilocarpine-TLE model
as many patients that die of SUDEP have TLE, and the DS model, as patients with DS have a
disproportionately high SUDEP risk. We will also determine whether simply having epilepsy in these
models impairs CO2-arousal as a potential easily measurable biomarker for SUDEP risk. In Aim 2 we will
determine whether neuronal function, assessed via fiber photometry, of arousal system components in
the dorsal raphe nucleus and parabrachial nucleus, two important contributors to sleep-wake regulation
and key nodes in CO2-arousal, is impaired by seizures and epilepsy. In Aim 3 we will determine whether
optogenetically stimulating a DRN-PBN circuit in DS mice, using a novel mouse model, prior to seizures
prevents seizure-induced death lending direct insights into possible therapeutic measures. Since the
models employed have known death rates, we will be able to compare findings between mice that die
and those that survive making these studies more relevant to SUDEP. Combining these findings with our
previous work, we will have a powerful, rigorous, translatable approach to identify convergent and
divergent mechanisms across models for how impaired CO2-arousal in epilepsy contributes to SUDEP
risk. We expect to be able to leverage these mechanisms to identify at-risk individuals and reduce death
from this devastating disease.
抽象的
癫痫(SUDEP)突然意外死亡是难治性患者死亡的主要原因
癫痫。 Sudep在失去神经系统疾病的几年中仅次于中风,这是
主要的公共卫生问题。已经提出了几种病因,包括心脏和心脏的SUDEP
呼吸失调。另一个发布的是唤醒。癫痫发作障碍。之中
唤醒刺激,可能与SUDEP特别相关的刺激是二氧化碳。癫痫发作后二氧化碳升高和
是扣除戒烟机制的一部分。癫痫发作经常与发作和污染后有关
中央和阻塞性呼吸暂停。呼吸暂停进一步加剧了二氧化碳的积累。二氧化碳的损害
提出唤醒作为另一个猝死实体的病因学因素
综合征,与Sudep有许多相似之处。我们发现癫痫发作受损
癫痫发作的小鼠和那些没有特别深刻的死亡率的小鼠。这是否是真的
具有强大SUDEP表型的小鼠模型尚不清楚。那就是我们在此提案中的目标是确定
不同睡眠状态的癫痫
(TLE)和遗传性癫痫性脑病,Dravet综合征(DS)。在AIM 1中,我们将确定
在癫痫模型中,二氧化碳曲线受损的程度。我们将重点放在毛果皮式模型上
由于许多死于SUDEP的患者具有TLE,并且DS模型,因为DS患者具有
不成比例的SUDEP风险。我们还将确定是否简单地癫痫
模型会损害CO2-AROUSAL,这是一种易于测量的SUDEP风险的潜在可测量的生物标志物。在目标2中,我们将
确定通过纤维光度法评估的神经元功能是否唤醒系统成分
背侧raphe核和副核核,这是睡眠效果调节的两个重要因素
二氧化碳和癫痫病损害的二氧化碳和关键淋巴结受损。在AIM 3中,我们将确定是否
在癫痫发作之前,使用新型小鼠模型在DS小鼠中刺激DS小鼠的DRN-PBN电路
防止癫痫发作引起的死亡贷款直接洞察可能的治疗措施。自从
所使用的模型已知死亡率,我们将能够比较死亡的小鼠之间的发现
那些幸存下来的研究使这些研究与SUDEP更相关。将这些发现与我们
以前的工作,我们将采用强大,严格,可翻译的方法来识别融合和
模型跨模型的发散机制,癫痫病中的二氧化碳核能受损如何有助于Sudep
风险。我们希望能够利用这些机制来识别高风险的人并减少死亡
来自这种毁灭性疾病。
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)
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Gordon Frank Buchanan其他文献
Gordon Frank Buchanan的其他文献
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{{ truncateString('Gordon Frank Buchanan', 18)}}的其他基金
Serotonergic circuit mechanisms in postictal recovery and arousal
发作后恢复和唤醒中的血清素回路机制
- 批准号:
10562496 - 财政年份:2022
- 资助金额:
$ 2.78万 - 项目类别:
Sleep state-dependent mechanisms of seizure-induced death
癫痫引起的死亡的睡眠状态依赖性机制
- 批准号:
9900880 - 财政年份:2016
- 资助金额:
$ 2.78万 - 项目类别:
Sleep state-dependent mechanisms of seizure-induced death
癫痫引起的死亡的睡眠状态依赖性机制
- 批准号:
10118793 - 财政年份:2016
- 资助金额:
$ 2.78万 - 项目类别:
Sleep state-dependent mechanisms of seizure-induced death
癫痫引起的死亡的睡眠状态依赖性机制
- 批准号:
9428205 - 财政年份:2016
- 资助金额:
$ 2.78万 - 项目类别:
Serotonin neurons in arousal, epilepsy and SUDEP
唤醒、癫痫和 SUDEP 中的血清素神经元
- 批准号:
8849987 - 财政年份:2015
- 资助金额:
$ 2.78万 - 项目类别:
Serotonin neurons in arousal, epilepsy and SUDEP
唤醒、癫痫和 SUDEP 中的血清素神经元
- 批准号:
9026191 - 财政年份:2015
- 资助金额:
$ 2.78万 - 项目类别:
Serotonin neurons in arousal, epilepsy and SUDEP.
唤醒、癫痫和 SUDEP 中的血清素神经元。
- 批准号:
8472546 - 财政年份:2011
- 资助金额:
$ 2.78万 - 项目类别:
Serotonin neurons in arousal, epilepsy and SUDEP.
唤醒、癫痫和 SUDEP 中的血清素神经元。
- 批准号:
8045210 - 财政年份:2011
- 资助金额:
$ 2.78万 - 项目类别:
Serotonin neurons in arousal, epilepsy and SUDEP.
唤醒、癫痫和 SUDEP 中的血清素神经元。
- 批准号:
8225304 - 财政年份:2011
- 资助金额:
$ 2.78万 - 项目类别:
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