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.