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.

项目总结/摘要 癫痫猝死（Sudden unexpected death in epilepsy，SUDEP）仍然是癫痫患者及其家属的一个主要问题。 家庭SUDEP的发生率估计为1 - 2.5/1000患者年，但基础疾病 原因知之甚少。在这里，我们将讨论腺苷假说的SUDEP。癫痫发作 触发腺苷（ADO）激增，腺苷是终止癫痫发作所需的内源性药物，但 还通过激活不同亚型的腺苷受体来控制脑干中的呼吸功能 （AR）。我们的总体假设是，在与不充分的 ADO在脑干中的代谢清除可引起致命的AR过度激活，导致脑干 调节异常和呼吸功能障碍是SUDEP的诱因。为了支持我们的假设，我们 证明了非选择性AR拮抗剂（咖啡因）减少了啮齿动物模型中的致死性呼吸暂停。 癫痫和创伤性脑损伤我们的初步数据支持ADO 代谢、AR激活和致死性呼吸暂停。基于这些原因我们的建议集中在脑干- SUDEP的依赖性呼吸机制。 具体来说，我们将讨论我们的中心假设，即SUDEP的易感性与以下因素有关： 在脑干的呼吸区域中异常的ADO代谢和信号传导， 增强ADO的代谢清除或阻断AR活化的治疗干预。脑干 具体的操作将允许我们测试ADO在脑干中的具体作用。解剖相关 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ADO操作提供一条翻译途径，以预防SUDEP。我们的模型 系统是一种“SUDEP易感小鼠”，由于杂合破坏，ADO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ADK的主要代谢清除途径。 在大脑中。我们的研究目标将在3个具体目标：（1）测试假设，SUDEP是 与ADO代谢的适应不良变化有关。(2)测试假设咖啡因在 SUDEP易感性。(3)测试抑制A2 AR激活是否可以预防SUDEP。预期 这项研究的结果是证明，代谢清除的能力， ADO通过脑干决定SUDEP的易感性。机制研究将确定AR 涉及的亚型。此外，这项研究将有助于澄清长期使用咖啡因是否有益 或对癫痫患者构成危险因素。最后，我们将测试A2 AR拮抗剂， 已经在临床上开发用于治疗帕金森病，可以预防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