Sequence of physiological events during oxygen conserving reflex activation leading to sudden death in epilepsy

节氧反射激活期间导致癫痫猝死的生理事件序列

• 批准号: 10622708
• 负责人: Pedro Irazoqui
• 金额: $ 7.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622708
• 关键词: Acute; Affect; Animal Experiments; Animal Model; Animals; Apnea; Blood specimen; Carotid Body; Cessation of life; Chronic; Clinical; Data; Development; Devices; Disease; Drug Delivery Systems; Epilepsy; Event; Intervention; Lead; Light; Measurement; Mediating; Methods; Modeling; Neuraxis; Neurotransmitters; Oxygen; Pathway interactions; Patients; Peripheral; Pharmacologic Substance; Pharmacology; Physiological; Play; Reflex action; Research; Respiration; Respiratory Failure; Risk; Role; Seizures; Serotonin; Signal Pathway; Signal Transduction; Structure; Sudden Death; Techniques; Therapeutic; United States; Up-Regulation; Ursidae Family; Work; clinical diagnostics; clinical translation; experimental study; insight; prevent; respiratory; screening; sudden unexpected death in epilepsy; treatment strategy

Project Summary Recent SUDEP research points to serotonin as a key neurotransmitter involved in apnea and death, but most research into serotonin signaling pathways focuses on serotonin signaling in the central nervous system. Our animal experiments modeling SUDEP have shown that the carotid body, a peripheral structure, plays a major role in the progression of fatal apnea. I will explore how peripheral intervention through the carotid body impacts respiration by observing how serotonin and serotonergic compounds affect oxygen conserving reflexes during acute seizure experiments (Aim 1) and using photopharmacology (light-mediated drug delivery) to localize pharmaceutical interventions to the carotid body (Aim 2) in acute seizure experiments with oxygen conserving reflexes. Aim 1 will probe serotonin mechanisms in ictal respiratory crisis from our animal model that we can compare to mechanisms observed in clinical seizure cases. This may further validate the animal SUDEP model and could also imply an effective way to stratify SUDEP risk for patients. Aim 1 will help answer whether promoting serotonin signaling can prevent respiratory failure leading to sudden death. Administering serotonin intracranially and systemically will help explore how seizure affects serotonin signaling pathways and determine whether systemic upregulation of serotonin can mitigate these effects. Similarly, administering serotonergic compounds will provide insight into how pharmaceutical treatments prescribed for other serotonin disorders impact respiration during seizure. Aim 2 will explore how targeted serotonin administration affects respiratory pathways implicated in SUDEP. Photocaged serotonin will enable me to only administer serotonin to a region illuminated with the proper wavelength of light. This will clarify the role of the carotid body in respiratory signaling and, if photorelease of serotonin succeeds in preventing sudden death, this could lead to the development of a chronic device to prevent SUDEP in at-risk patients. In addition to yielding useful, fundamental mechanistic data about how serotonin impacts respiratory crisis, both inside and outside seizure, the techniques used to generate this data also bear clinical translation relevance. The experimental methods developed here may reasonably transition to practical clinical diagnostic and therapeutic strategies.

项目摘要 最近的SUDEP研究指出，血清素是参与呼吸暂停和死亡的关键神经递质，但大多数 对5-羟色胺信号通路的研究集中在中枢神经系统中的5-羟色胺信号。我们 模拟SUDEP的动物实验已经表明，颈动脉体，一种外周结构， 在致命性呼吸暂停进展中的作用。我将探讨如何通过颈动脉体进行外周干预 通过观察血清素和β-羟色胺能化合物如何影响氧气保存来影响呼吸 急性癫痫发作实验（目的1）和使用光药理学（光介导的药物递送）期间的反射 在氧气急性癫痫发作实验中将药物干预定位于颈动脉体（目的2） 保存反射 目的1将探讨5-羟色胺机制在发作性呼吸危象从我们的动物模型，我们可以比较， 在临床癫痫病例中观察到的机制。这可以进一步验证动物SUDEP模型， 这也意味着一种有效的方法来分层SUDEP的风险为患者。 Aim 1将有助于回答促进血清素信号传导是否可以预防呼吸衰竭导致的突发性 死亡颅内和全身给予血清素将有助于探索癫痫发作如何影响血清素 信号通路，并确定是否全身上调5-羟色胺可以减轻这些影响。 类似地，给予多巴胺能化合物将提供对药物治疗如何 用于治疗其他血清素紊乱的药物会影响癫痫发作时的呼吸。 目的2将探讨如何有针对性的5-羟色胺管理影响呼吸通路牵连SUDEP。 光笼化的血清素能让我只把血清素注射到 光的波长这将阐明颈动脉体在呼吸信号传导中的作用，并且如果光释放 5-羟色胺成功地防止了猝死，这可能导致一种慢性装置的发展， 预防高危患者的SUDEP。 除了产生关于血清素如何影响呼吸危象的有用的、基本的机理数据外， 无论是在癫痫发作的内部还是外部，用于生成这些数据的技术也具有临床意义。 本案无关本文所发展的实验方法可以合理地过渡到实际的临床诊断 和治疗策略。