Adenosine receptor mediated therapies for SUDEP

腺苷受体介导的 SUDEP 疗法

• 批准号: 10409789
• 负责人: Detlev Boison
• 金额: $ 34.34万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409789
• 关键词: ADORA2A gene; Acute; Address; Adenosine; Adenosine Kinase; Affect; Apnea; Astrocytes; Benefits and Risks; Biological Models; Brain; Brain Stem; Caffeine; Chronic; Consumption; Crossover Design; Data; Dissection; Dose; Drops; Enterobacteria phage P1 Cre recombinase; Epilepsy; Family; Genes; Goals; Impairment; Incidence; Intake; Limbic System; Link; LoxP-flanked allele; Mediating; Metabolic; Metabolism; Molecular; Mus; Outcome; Outcomes Research; Parkinson Disease; Pathway interactions; Patients; Persons; Physiological; Play; Predisposition; Prevention; Property; Purinergic P1 Receptors; Receptor Gene; Recommendation; Research; Respiration; Respiration Disorders; Respiratory Center; Respiratory System; Respiratory physiology; Risk; Risk Factors; Rodent Model; Role; Route; Seizures; Signal Transduction; Sleep; System; Testing; Therapeutic; Therapeutic Intervention; Time; Translating; Traumatic Brain Injury; Viral; Wild Type Mouse; Withdrawal; adenosine receptor activation; antagonist; base; clinical development; clinically relevant; design; feasibility testing; mouse model; novel; overexpression; prevent; receptor; reconstitution; respiratory; response; sudden unexpected death in epilepsy; therapy development

Project Summary/Abstract Sudden unexpected death in epilepsy (SUDEP) remains a major concern for persons with epilepsy and their families. The incidence of SUDEP is estimated at 1 to 2.5 per 1000 patient years however the underlying reasons are poorly understood. Here we will address the adenosine hypothesis of SUDEP. Epileptic seizures trigger a surge of adenosine (ADO), which is an endogenous agent required for seizure termination, but which also controls respiratory functions in the brainstem by activation of different subtypes of adenosine receptors (ARs). Our overarching hypothesis is that a seizure-induced increase in ADO in combination with insufficient metabolic clearance of ADO in the brainstem can cause fatal over-activation of ARs leading to brainstem dysregulation and respiratory dysfunction as a precipitator of SUDEP. In support of our hypothesis, we demonstrated that a non-selective AR antagonist (caffeine) reduced lethal apnea in rodent models of epilepsy and traumatic brain injury. Our preliminary data support a strong association between ADO metabolism, AR activation, and lethal apnea. For those reasons we focus our proposal on the brainstem- dependent respiratory mechanisms of SUDEP. Specifically, we will address our central hypothesis that the susceptibility to SUDEP is related to abnormal ADO metabolism and signaling in respiratory regions of the brainstem and preventable by therapeutic interventions that enhance metabolic clearance of ADO or block AR activation. Brainstem specific manipulations will allow us to test a specific role of ADO in the brainstem. Dissection of seizure-related functions of ADO metabolism and signaling in the limbic system from respiratory control functions in the brainstem will enable a translational path for ADO-manipulation for the prevention of SUDEP. Our model system is a `SUDEP-prone mouse' with impaired metabolic clearance of ADO due to a heterozygous disruption of the adenosine kinase (Adk) gene. ADK, expressed in astrocytes is the main metabolic clearance route for ADO in the brain. Our research goals will be approached in 3 Specific Aims: (1) Test hypothesis that SUDEP is associated with maladaptive changes in ADO metabolism. (2) Test hypothesis that caffeine plays a critical role in SUDEP susceptibility. (3) Test whether suppression of A2AR activation can prevent SUDEP. The expected outcome of this research is the demonstration that the capacity for the metabolic clearance of seizure-induced ADO through the brainstem determines susceptibility to SUDEP. Mechanistic studies will identify the AR subtypes involved. In addition, this research will help to clarify whether the chronic use of caffeine is of benefit or presents a risk factor for persons with epilepsy. Finally, we will test whether A2AR antagonists, which are already in clinical development for the treatment of Parkinson's disease, can prevent SUDEP.

项目摘要/摘要 癫痫（SUDEP）突然意外死亡仍然是癫痫患者及其他们的主要关注点 家庭。 SUDEP的发生率估计为每1000名患者年1至2.5 理解的原因很少。在这里，我们将解决SUDEP的腺苷假说。癫痫发作 触发腺苷激增（ADO），这是癫痫发作所需的内源性药物，但 还通过激活腺苷受体的不同亚型来控制脑干中的呼吸功能 （ars）。我们的总体假设是，癫痫发作引起的ADO增加与不足 ADO在脑干中的代谢清除率会导致ARS的致命过度激活导致脑干 作为SUDEP的脱水剂的功能障碍和呼吸障碍。为了支持我们的假设，我们 证明非选择性AR拮抗剂（咖啡因）在啮齿动物模型中降低致命呼吸暂停 癫痫和脑部损伤。我们的初步数据支持ADO之间的密切关联 代谢，AR激活和致命呼吸暂停。由于这些原因，我们将建议重点放在脑干上 - SUDEP的依赖呼吸机制。 具体而言，我们将解决我们的核心假设，即SUDEP的易感性与 ADO代谢异常和脑干呼吸区的信号传导，可预防 可以增强ADO或阻断AR激活的代谢清除率的治疗干预措施。脑干 特定的操作将使我们能够测试ADO在脑干中的特定作用。癫痫发作相关的解剖 ADO代谢和信号传导在边缘系统中的功能来自呼吸控制功能 脑干将为预防SUDEP的适应操作提供转化路径。我们的模型 系统是一种“ SUDEP鼠标”，由于杂合破坏而导致ADO的代谢清除受损 腺苷激酶（ADK）基因。在星形胶质细胞中表达的ADK是主要的代谢清除途径 大脑中的ADO。我们的研究目标将以3个具体目的实现：（1）Sudep是 与ADO代谢的不良适应性变化有关。 （2）检验假设咖啡因起着至关重要的作用 在Sudep敏感性中。 （3）测试抑制A2AR激活是否可以防止SUDEP。预期 这项研究的结果表明，癫痫发作的代谢清除能力 通过脑干的ADO决定了对Sudep的敏感性。机械研究将确定AR 涉及的子类型。此外，这项研究将有助于阐明长期使用咖啡因是否有益 或给癫痫患者带来危险因素。最后，我们将测试A2AR对手是否是 在治疗帕金森氏病的临床发展中，已经可以防止SUDEP。

项目成果

The Purinome and the preBötzinger Complex - A Ménage of Unexplored Mechanisms That May Modulate/Shape the Hypoxic Ventilatory Response.

嘌呤组和 preBötzinger 复合物 - 可能调节/塑造缺氧通气反应的一系列未探索的机制。

• DOI: 10.3389/fncel.2019.00365
• 发表时间: 2019
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Reklow,RobertJ;Alvares,TucaaueS;Zhang,Yong;MirandaTapia,AnaP;Biancardi,Vivian;Katzell,AlexisK;Frangos,SaraM;Hansen,MeganA;Toohey,AlexanderW;Cass,CarolE;Young,JamesD;Pagliardini,Silvia;Boison,Detlev;Funk,GregoryD
• 通讯作者: Funk,GregoryD