Targeting cellular senescence to prevent epileptogenesis

针对细胞衰老预防癫痫发生

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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神经系统疾病，影响着 6500 万人它被认为是多种神经退行性疾病的共病，包括阿尔茨海默病 (AD)。确定预防癫痫发展（即癫痫发生）的目标是一个巨大的未满足的需求。即使在临床前模型中，抗癫痫治疗仍然有限。在这里，我们建议研究一种新颖的药物。目标是大脑中的衰老细胞（SC），以确定消除这些细胞是否可以预防大脑中的癫痫发生毛果芸香碱颞叶癫痫小鼠模型和伴有共病的 AD 小鼠 APdE9 模型细胞衰老是一种保守的细胞程序，它会停止增殖并触发促细胞分裂。炎症衰老相关分泌表型（SASP）对损伤性刺激的反应。人们对神经退行性疾病的兴趣日益浓厚，但在癫痫方面仍然完全未经探索。癫痫持续状态 (SE) 等致癫痫损伤会强烈引发 DNA 损伤，这是细胞损伤的常见原因。此外，在癫痫发生期间报道的促炎细胞因子谱具有惊人的特征。与 SASP 相似，我们将使用 INK-ATTAC 小鼠模型，该模型选择性表达诱导型。 p16 启动子控制下的自杀基因（和 GFP）；p16 表达是 SC 的标志。我们将首先确定毛果芸香碱诱导 SE 后 p16 阳性细胞的细胞特性（胶质细胞、神经元）。接下来我们将确定消融 SC 是否会减少 SE 后促炎细胞因子的表达。确定消融 SC 是否会减少自发性癫痫发作的发展和/或减少在目标 2 中，我们将针对具有不同病因的模型，即 APdE9 小鼠模型。 AD，显示共病癫痫发作和 SC 积累，如目标 1 所示，我们将首先描述 AD 的特征。 APdE9 模型中 SC 的细胞表型接下来我们将确定 SC 的消融是否会减少促炎性。最后，我们将确定 SC 的消融是否会减少自发性癫痫发作。 APdE9 小鼠中的发生通过使用两种模型，具有非常不同的病因和“临床”表现。（毛果芸香碱后的惊厥性癫痫发作，APdE9 模型中的非惊厥性癫痫发作），我们准备测试总体假设是 SC 导致自发性癫痫发作的出现与仅针对特定细胞衰老模型的效应相比，癫痫发生具有重要意义。尚未对癫痫进行检查，因此，这些研究有可能开辟新的研究领域癫痫发生的机制。