Autoresuscitation and SUDEP

自动复苏和 SUDEP

• 批准号: 10598136
• 负责人: Kristina A Simeone
• 金额: $ 35.98万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598136
• 关键词: Acute; Air; Animal Model; Anticonvulsants; Apnea; Area; Blood gas; Breathing; Data; Deterioration; Disease; Epilepsy; Event; Exhibits; Failure; Goals; Hypercapnia; Hypothalamic structure; Hypoxia; Impairment; Individual; Intractable Epilepsy; Knockout Mice; Lateral; Life; Longevity; Maintenance; Metabolic; Molecular Target; Motor Seizures; Mus; Neurons; Neuropeptides; Patients; Persons; Pharmacotherapy; Pre-Clinical Model; Predisposition; Probability; Prone Position; Publishing; Qualifying; Recovery; Recurrence; Refractory; Reporting; Research; Respiratory physiology; Risk; Risk Assessment; Seizures; Series; Technical Expertise; Testing; Therapeutic; antagonist; clinically relevant; experience; hypocretin; in vivo; locus ceruleus structure; mortality; mouse model; nervous system disorder; neuropathology; neuroregulation; novel; pre-clinical; preBotzinger complex; preclinical study; programs; receptor; respiratory; response; sudden unexpected death in epilepsy; support network

Project Summary Approximately 30% of people with epilepsy are refractory to current anti-seizure medications and sudden unexpected death in epilepsy (SUDEP) occurs in ~1:150 per year for individuals with severe refractory generalized convulsive seizures (GCS). The long-term goals of our research program are to identify novel molecular targets with disease-modifying effects that may increase longevity in those susceptible to SUDEP. Evidence from the multi- center MORTEMUS study on SUDEP indicates that patients experienced a series of events promoting hypoxic and hypercapnic (HH) fluctuations in blood gases, from which they were unable to autoresuscitate and succumbed to terminal apnea. However, the relationship between SUDEP risk and the efficacy of the autoresuscitation response is unknown. The objective of the proposed project is to elucidate mechanisms of autoresuscitation failure in relation to SUDEP risk. The central hypothesis is that alterations in the network of chemosensitive cardiorespiratory neurons increases the probability of autoresuscitation failure and SUDEP risk. Our rationale is that SUDEP is often associated with a preceding GCS, but demise has also been associated with prone positions with no evidence of seizure. A variable or decline in autoresuscitation efficacy may explain succumbing to one GCS and not previous seizures or failing to arouse in situations of changing air supply. Our specific aims will test the hypotheses that maladaptive modulatory control of key central autoresuscitation centers disintegrates the network chemoresponse, causing deterioration of the response and the autoresuscitation response to fail. Upon conclusion, we will have delineated mechanisms underlying autoresuscitation failure in the context of epilepsy in a clinically relevant animal model of SUDEP. This information will offer new research avenues for understanding SUDEP, assessing risk and identifying therapeutic opportunities.

项目摘要 大约30%的癫痫患者对目前的抗癫痫药物难治， 癫痫意外死亡（SUDEP）发生在约1：150每年的个人严重难治性全身性癫痫 惊厥发作（GCS）。我们研究计划的长期目标是确定新的分子靶点 具有改善疾病的作用，可能会延长那些易受SUDEP影响的人的寿命。从多方面的证据- MORTEMUS中心对SUDEP的研究表明，患者经历了一系列促进缺氧的事件 和高碳酸血症（HH）的血液气体波动，他们无法自行复苏和死亡 到晚期呼吸暂停然而，SUDEP风险与自动复苏效果之间的关系 答案未知。该项目的目的是阐明自动复苏失败的机制 关于SUDEP风险。中心假设是，化学敏感网络的改变， 心肺神经元的损伤增加了自动复苏失败和SUDEP风险的可能性。我们的理据是 SUDEP通常与先前的GCS有关，但死亡也与俯卧位有关 没有证据表明是癫痫发作自动复苏效果的变化或下降可以解释屈服于一个 GCS，而不是以前的癫痫发作或未能在改变空气供应的情况下唤醒。我们的具体目标将测试 关键中枢自动复苏中心的适应不良调节控制瓦解了 网络化学反应，导致反应恶化和自动复苏反应失败。后 结论，我们将在癫痫背景下描述自动复苏失败的机制， SUDEP的临床相关动物模型。这些信息将提供新的研究途径， SUDEP，评估风险并确定治疗机会。