Targeting cellular senescence to prevent epileptogenesis

针对细胞衰老预防癫痫发生

• 批准号: 10362263
• 负责人: Patrick Alexander Forcelli
• 金额: $ 42.9万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10362263
• 关键词: APP-PS1; Abbreviations; Ablation; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Antiepileptogenic; Beds; Brain; Cell Aging; Cells; Chronic; Clinical; Cognitive deficits; Complement; DNA Damage; Data; Development; Disease; Emergency Situation; Epilepsy; Epileptogenesis; Etiology; Functional disorder; Hippocampus (Brain); Impaired cognition; Individual; Inflammation; Inflammatory; Injury; Link; Metalloproteases; Modeling; Monitor; Motor Seizures; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Patients; Phenotype; Pilocarpine; Population; Positioning Attribute; Pre-Clinical Model; Proliferating; Recurrence; Reporting; Research; Seizures; Status Epilepticus; Stimulus; Tauopathies; Temporal Lobe Epilepsy; Testing; behavioral impairment; brain dysfunction; cell injury; cell type; cellular targeting; chemokine; comorbidity; cytokine; cytotoxic; human model; interest; mouse model; novel; prevent; programs; promoter; response; selective expression; senescence; suicide gene; tool

Project Abstract Epilepsy is a chronic neurological condition characterized by recurrent seizures, affecting 65 million individuals and is recognized as a comorbidity in several neurodegenerative diseases, including Alzheimer’s disease (AD). Identifying targets to prevent the development of epilepsy (i.e., epileptogenesis) is a large unmet need. Antiepileptogenic therapies remain limited, even in preclinical models. Here, we propose to examine a novel target, senescent cells (SCs) in the brain, to determine if ablating these cells can prevent epileptogenesis in the pilocarpine mouse model of temporal lobe epilepsy and in the APdE9 mouse model of AD with comorbid epilepsy. Cellular senescence is a conserved cellular program which halts proliferation and triggers a pro- inflammatory senescence associated secretory phenotype (SASP) in response to damaging stimuli. SCs are of growing interest in neurodegenerative diseases but remain completely unexplored in the context of epilepsy. Epileptogenic insults, such as status epilepticus (SE) robustly trigger DNA damage, a common cause of cellular senescence. Moreover, the pro-inflammatory cytokine profile reported during epileptogenesis shares striking similarities to the SASP. We will use the INK-ATTAC mouse model, which selectively expresses an inducible suicide gene (and GFP) under the control of the p16 promoter; p16 expression is a hallmark of SCs. In Aim 1, we will first determine the cellular identity (glial, neuronal) of p16 positive cells following pilocarpine-induced SE. We will next determine if ablating SCs reduces proinflammatory cytokine expression after SE. Finally, we will determine if ablating SCs reduces the development of spontaneous seizures and/or reduces expression of seizures once they occur. In Aim 2, we will target a model with a different etiology, the APdE9 mouse model of AD, which displays co-morbid seizures, and accumulation of SCs. As in Aim 1, we will first characterize the cellular phenotype of SCs in the APdE9 model. We will next determine if ablation of SCs reduces proinflammatory cytokine levels in APdE9 mice. Finally, we will determine if ablation of SCs reduces spontaneous seizure occurrence in APdE9 mice. By using two models, with very different etiologies and “clinical” presentation (convulsive seizures after pilocarpine, non-convulsive seizures in the APdE9 model), we are positioned to test the overarching hypothesis that SCs contribute to the emergence of spontaneous seizures during epileptogenesis, as compared to an effect that is specific to only a particular model. Cellular senescence is unexamined in epilepsy, thus, these studies have the potential to open new lines of research into the mechanisms of epileptogenesis.

项目摘要 癫痫是一种以反复发作为特征的慢性神经系统疾病，影响6500万人 并且被认为是包括阿尔茨海默病（AD）在内的几种神经退行性疾病的共病。 确定预防癫痫发展的目标（即，癫痫发生）是一个很大的未满足的需求。 抗癫痫治疗仍然有限，即使在临床前模型。在这里，我们打算研究一部小说， 靶向大脑中的衰老细胞（SC），以确定消融这些细胞是否可以预防癫痫发生。 颞叶癫痫的匹鲁卡品小鼠模型和AD与共病的APdE 9小鼠模型 癫痫细胞衰老是一种保守的细胞程序，它阻止增殖并触发促衰老反应。 炎性衰老相关分泌表型（SASP）。SC为 对神经退行性疾病的兴趣日益增长，但在癫痫的背景下仍然完全未被探索。 致痫性损伤，如癫痫持续状态（SE）强烈触发DNA损伤，这是细胞损伤的常见原因。 衰老此外，在癫痫发生过程中报道的促炎性细胞因子谱与癫痫发病机制有着惊人的相似性。 与SASP相似。我们将使用INK-ATTAC小鼠模型，该模型选择性地表达可诱导的 在p16启动子控制下的自杀基因（和GFP）; p16表达是SC的标志。在目标1中， 我们将首先确定匹鲁卡品诱导SE后p16阳性细胞的细胞特性（神经胶质、神经元）。 我们接下来将确定消融SC是否减少SE后促炎细胞因子的表达。最后我们将 确定消融SC是否减少自发性癫痫发作的发展和/或减少 一旦发作。在目标2中，我们将靶向具有不同病因的模型，即， AD，其显示共病癫痫发作和SC积累。与目标1一样，我们将首先描述 在APdE 9模型中SC的细胞表型。我们接下来将确定SC的消融是否减少了促炎性细胞因子， APdE 9小鼠的细胞因子水平。最后，我们将确定是否消融SC减少自发性癫痫发作 在APdE 9小鼠中发生。通过使用两种模型，具有非常不同的病因和“临床”表现 （匹鲁卡品后惊厥性发作，APdE 9模型中的非惊厥性发作），我们定位于测试 总体假设，即SC有助于自发性癫痫发作的出现， 癫痫发生，与仅特定于特定模型的效应相比。细胞衰老是 因此，这些研究有可能开辟新的研究领域， 癫痫发生的机制