The contribution of cellular senescence in epileptogenesis

点击翻译按钮获取中文摘要

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.