The contribution of cellular senescence in epileptogenesis

细胞衰老在癫痫发生中的贡献

• 批准号: 10669595
• 负责人: Tahiyana Khan
• 金额: $ 3.6万
• 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: 2022-07-15 至 2024-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669595
• 关键词: Ablation; Acceleration; Acute; Animal Model; Antiepileptic Agents; Antiepileptogenic; Area; Behavioral; Bioinformatics; Biology; Cell Aging; Cell Proliferation; Cells; Chronic; Cognitive deficits; Committee Members; DNA Damage; Data; Data Set; Deterioration; Development; Disease; Doctor of Philosophy; Educational process of instructing; Educational workshop; Electroencephalography; Ensure; Epilepsy; Epileptogenesis; Excision; Fellowship; Freedom; Functional disorder; Gene Expression Profile; Genes; Genetic; Goals; Grant; Health; Hippocampus; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Injury; Institution; Laboratories; Lead; Learning; Manuscripts; Medical; Memory; Memory impairment; Mentors; Mentorship; Methods; Microglia; Modeling; Mus; Nerve Degeneration; Nervous System Trauma; Neurons; Neurosciences; Oxidative Stress; Pathologic; Pharmacotherapy; Phase; Phenotype; Play; Positioning Attribute; Postdoctoral Fellow; Pre-Clinical Model; Process; Proliferating; Publishing; Recurrence; Research; Research Personnel; Research Project Grants; Resources; Role; Seizures; Status Epilepticus; Stimulus; Students; Symptoms; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Training; Universities; Writing; acquired epilepsy; age related; career; cell injury; cytokine; druggable target; improved; in vivo; innovation; interest; metabolomics; mouse model; nano-string; neuron loss; novel; post-doctoral training; pre-doctoral; prevent; programs; response; senescence; skills; spatial memory; success; symposium; timeline; transcriptomics

Temporal lobe epilepsy (TLE), the most common form of acquired epilepsy, displays a high rate of medically-intractable seizures. TLE is caused by damage to the temporal lobe, which leads both to spontaneous seizures and in some cases, cognitive impairment. Identifying strategies to disrupt epileptogenesis (the process by which epilepsy develops) may thus be advantageous. TLE is modeled in animal models by inducing prolonged seizures (status epilepticus [SE]) and causes significant pathological changes such as neuronal death, DNA damage, oxidative stress, and inflammation. These cellular responses are also common hallmarks of cellular senescence, a conserved cellular program which halts proliferation of damaged cells. Senescent cell (SC) accumulation actively drives naturally occurring age-related deterioration by secreting pro-inflammatory cytokines known as the senescence associated secretory phenotype (SASP) and contributes to neurodegeneration. Cellular senescence in epilepsy has not been previously examined. I propose to investigate the involvement of cellular senescence in exacerbating spontaneous recurrent seizures (SRS) and cognitive impairments following epileptogenic insult. My data indicate that SCs accumulate following SE, and the SCs that accumulate are predominantly microglia. Further, my data suggest that SC ablation reduces seizure burden and improves spatial memory deficits following epileptogenic insult. This F99/K00 proposal will encompass 2 aims presented in the following research plan. In Aim 1, I have outlined my proposed hypotheses for my dissertation (F99 component). I will characterize the microglial senescence profile after chronic epilepsy develops and determine how SC ablation alters microglial transcriptional signatures, as well as test the hypothesis that SC removal alleviates seizure burden and cognitive deficits associated with TLE. The proposed research will benefit the field by examining a novel cellular mechanism underlying epileptogenesis and associated cognitive impairments. I will learn transcriptomics, EEG, and behavioral methods and analysis. After completing my PhD, I will continue to build skills in a post-doctoral setting, exploring the senescence processes that accelerate neurodegeneration through omics methods and analyses. I will achieve this goal by identifying an ideal post-doctoral laboratory. My goal for the K00 component is to complete my post- doctoral training at an institution that values rigorous scientific research, innovation, diversity, and professional development. My sponsor and I have been heavily committed to prepare me for this next step of my long-term goal of becoming an independent investigator, by working with my dissertation committee, presenting and networking at multiple conferences and workshops, and inviting investigators in my field to Georgetown University. The F99/K00 will catalyze my goals for a successful PhD and obtaining a postdoctoral position.

颞叶癫痫（TLE）是最常见的获得癫痫的形式，显示出很高的率 可扣除的癫痫发作。 TLE是由颞叶损坏引起的，这两者都会自发 癫痫发作，在某些情况下是认知障碍。确定破坏癫痫发生的策略（该过程 因此，癫痫发育可能是有利的。 TLE通过诱导延长的动物模型建模 癫痫发作（癫痫持续状态[SE]），并引起重大的病理变化，例如神经元死亡，DNA 损伤，氧化应激和炎症。这些细胞反应也是细胞的常见标志 衰老，一种保守的细胞程序，可以阻止受损细胞的增殖。 衰老细胞（SC）积累积极驱动自然发生的与年龄相关的恶化。 分泌促炎性细胞因子被称为衰老相关的分泌表型（SASP）和 有助于神经变性。先前尚未检查癫痫中细胞衰老。我建议 研究细胞衰老参与加重自发癫痫发作（SRS）和 癫痫侮辱后的认知障碍。我的数据表明，SC在SE之后积累，以及 积累的SC主要是小胶质细胞。此外，我的数据表明SC消融可减少癫痫发作 负担并改善了癫痫侮辱后的空间记忆缺陷。 该F99/K00提案将涵盖以下研究计划中提出的2个目标。在AIM 1中，我有 概述了我为论文（F99组件）提出的假设。我将描述小胶质的 慢性癫痫后的衰老特征发展并确定SC消融如何改变小胶质细胞 转录签名，并检验以下假设，即SC删除减轻了癫痫发作负担和认知 与TLE相关的缺陷。 拟议的研究将通过检查一种新的细胞机制来使该领域受益 癫痫发生和相关的认知障碍。我将学习转录组学，脑电图和行为方法 和分析。完成博士学位后，我将继续在博士后设置中建立技能，探索 通过OMICS方法和分析加速神经退行性的衰老过程。我会实现的 通过确定理想的博士后实验室的目标。我对K00组件的目标是完成我的职位 - 重视严格的科学研究，创新，多样性和专业的机构的博士培训 发展。我和我的赞助商一直致力于为我的长期下一步做好准备 通过与我的论文委员会合作，提出和 在多个会议和研讨会上进行联网，并邀请我的领域调查员到乔治敦 大学。 F99/K00将促进我成功获得博士学位并获得博士后职位的目标。