The contribution of cellular senescence in epileptogenesis

细胞衰老在癫痫发生中的贡献

• 批准号: 10540532
• 负责人: Tahiyana Khan
• 金额: $ 3.51万
• 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/10540532
• 关键词: Ablation; Acute; Address; 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 (Brain); 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; Pharmaceutical Preparations; 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; Students; Symptoms; Temporal Lobe; Temporal Lobe Epilepsy; Testing; TimeLine; 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; 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）是获得性癫痫最常见的形式，表现出高发病率。 难以治愈的癫痫颞叶癫痫是由颞叶损伤引起的， 癫痫发作，在某些情况下，认知障碍。确定中断癫痫发生的策略（该过程 癫痫由此发展）因此可能是有利的。TLE在动物模型中通过诱导延长的 癫痫发作（癫痫持续状态[SE]），并引起显著的病理变化，如神经元死亡，DNA 氧化应激和炎症。这些细胞反应也是细胞免疫反应的共同标志。 衰老是一种保守的细胞程序，可阻止受损细胞的增殖。 衰老细胞（SC）的积累通过以下方式主动驱动自然发生的与年龄相关的恶化： 分泌促炎细胞因子，称为衰老相关分泌表型（SASP）， 会导致神经退化癫痫中的细胞衰老以前没有被研究过。我提议 研究细胞衰老在自发性复发性癫痫发作（SRS）加重中的作用， 癫痫性损伤后的认知障碍。我的数据表明SC在SE之后积累， 聚集的SC主要是小胶质细胞。此外，我的数据表明，SC消融减少癫痫发作 减轻癫痫性损伤后的负担并改善空间记忆缺陷。 本F99/K 00提案将包括以下研究计划中提出的2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）。我会描述小胶质细胞 慢性癫痫发展后的衰老特征，并确定SC消融如何改变小胶质细胞 转录签名，以及测试的假设，SC去除加重癫痫发作的负担和认知 与TLE相关的缺陷。 拟议的研究将有利于该领域通过检查一种新的细胞机制， 癫痫发生和相关的认知障碍。我会学习转录组学脑电图和行为学方法 和分析完成博士学位后，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行性变的衰老过程。我将实现 通过确定一个理想的博士后实验室这一目标。我的目标是完成我的文章- 在一个重视严谨的科学研究，创新，多样性和专业性的机构进行博士培训 发展我的赞助商和我一直致力于为我的长期计划的下一步做好准备。 我的目标是成为一名独立的调查员，通过与我的论文委员会合作， 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/K 00将促进我成功获得博士学位并获得博士后职位的目标。