The contribution of cellular senescence in epileptogenesis

颞叶癫痫(TLE)是获得性癫痫最常见的形式，表现为高发病率。 医学上难以治愈的癫痫。TLE是由颞叶受损引起的，这导致两者都是自发的 癫痫发作，在某些情况下，认知障碍。确定阻断癫痫发生的策略(这一过程 癫痫的发展)因此可能是有利的。TLE的动物模型是通过诱导延长 癫痫发作(癫痫持续状态[SE])，并导致显著的病理变化，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共同特征 衰老是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)的积累通过以下方式积极地推动自然发生的与年龄相关的退化 分泌促炎细胞因子，称为衰老相关分泌表型(SASP)和 会导致神经退化。癫痫的细胞衰老以前还没有被研究过。我建议 探讨细胞衰老在加重自发性复发性癫痫(SRS)中的作用 致痫侮辱后的认知障碍。我的数据显示，SC在SE之后积累，而 积聚的干细胞主要是小胶质细胞。此外，我的数据表明，SC消融可以减少癫痫发作 增加癫痫发作后的负担，改善空间记忆缺陷。 这份F99/K00提案将包含以下研究计划中提出的两个目标。在目标1中，我有 概述了我为我的论文提出的假设(F99部分)。我会描述一下小胶质细胞的特征 慢性癫痫后的衰老特征及SC消融对小胶质细胞的影响 转录信号，以及检验去除SC可减轻癫痫负担和认知能力的假设 与TLE相关的缺陷。 这项拟议的研究将通过检测一种新的细胞机制来使该领域受益 癫痫的发生和相关的认知障碍。我将学习转录学、脑电波和行为方法 和分析。在完成我的博士学位后，我将继续在博士后环境中培养技能，探索 通过组学方法和分析加速神经退化的衰老过程。我会实现 这一目标是通过确定理想的博士后实验室来实现的。我对K00组件的目标是完成我的帖子- 在重视严谨科学研究、创新、多样化和专业的机构进行博士培训 发展。我的赞助人和我一直致力于为我的长期职业生涯的下一步做准备 目标是成为一名独立的研究员，通过与我的论文委员会合作，提交和 在多个会议和研讨会上建立联系，并邀请我所在领域的研究人员到乔治敦大学 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。

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.