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SUDEP的研究指出，5-羟色胺是与呼吸暂停和死亡有关的关键神经递质，但大多数 对5-羟色胺信号通路的研究主要集中在中枢神经系统中的5-羟色胺信号。我们的 模拟SUDEP的动物实验表明，颈动脉小体作为一种外周结构，在 在致命性呼吸暂停进展中的作用。我将探索如何通过颈动脉小体进行外周干预 通过观察5-羟色胺和5-羟色胺能化合物如何影响储氧来影响呼吸 急性癫痫发作实验中的反射(目标1)和使用光药理学(光中介药物传递) 急性氧气惊厥实验中对颈动脉小体的药物干预(目标2) 保存反射。 目标1将从我们的动物模型中探索5-羟色胺在发作期呼吸危象中的机制，我们可以与之进行比较 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，并可以 也意味着有一种有效的方法来对患者的SUDEP风险进行分层。 目标1将帮助回答促进5-羟色胺信号传递是否可以防止导致突然的呼吸衰竭 死亡。全身注射5-羟色胺有助于探索癫痫发作对5-羟色胺的影响 并确定系统地上调5-羟色胺是否可以减轻这些影响。 同样，应用5-羟色胺能化合物将提供对药物治疗的洞察 治疗其他5-羟色胺紊乱症的处方会在癫痫发作期间影响呼吸。 目的2将探讨靶向5-羟色胺给药如何影响SUDEP所涉及的呼吸通路。 照相笼子里的5-羟色胺将使我能够只给适当的照亮的区域注射5-羟色胺 光的波长。这将阐明颈动脉小体在呼吸信号中的作用，如果光释放 5-羟色胺成功预防猝死，这可能导致一种慢性设备的开发 预防高危患者的SUDEP。 除了提供关于5-羟色胺如何影响呼吸危机的有用的、基本的机械数据外， 无论是在癫痫的内部还是外部，用来产生这些数据的技术也适用于临床。 关联性。这里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。