# Functional analysis of the microRNA-induced silencing complex in epilepsy

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $124,901

## Abstract

SUMMARY: Acquired epilepsy is a chronic condition that requires life-long medication and is often drug-
resistant. The development of more efficient drugs to prevent or reduce epilepsy is currently hindered by a gap
in knowledge of how an epilepsy-precipitating event turns a healthy brain into a brain that produces spontaneous
recurrent seizures. This process, known as epileptogenesis, is thought to be highly complex. Halting or
preventing epileptogenesis thus most likely requires the concerted manipulation of many different molecular
networks and pathways. It is therefore plausible that treatment strategies targeting regulatory mechanisms that
control multiple of these cellular pathways at once will be most successful. This research will address this
challenge by analyzing how a potent regulator of the expression of hundreds of genes, the microRNA-induced
silencing complex (RISC), contributes to epileptogenic processes after status epilepticus (SE). Previous work
supports a role of microRNAs and the RISC in epilepsy development by showing that select microRNAs and
mRNAs are recruited to the RISC after seizure, and that inhibition of single microRNAs reduces seizure
susceptibility and epileptogenesis in rodent epilepsy models. Yet, the molecular mechanisms and pathways
underlying the seizure-mitigating effects of microRNA manipulation are largely unknown. The overall hypothesis
of this research is that SE induces changes in RISC and microRNA function that enhance epileptogenic and
decrease neuroprotective pathways. Inhibiting these changes may prevent or impair the development of
epilepsy. This hypothesis will be tested with two aims. Aim 1 will follow an unbiased approach using cell type-
specific immunoprecipitation of the RISC, RNA sequencing and genetic knockdown strategies to reveal the
nature and functional relevance of molecular pathways that are differentially regulated by the RISC after SE in
mice. Aim 2 will follow a candidate-based approach using ribosomal tagging and functional assays together with
antisense-mediated microRNA inhibition to reveal the cell-specific translatome of a pro-convulsive microRNA
and how it contributes to epileptogenesis after SE. Based on complementing expertise of neuroscientists and
computational biologists, the approach to perform screens of RISC and microRNA target regulation after SE
paired with pathway and functional analyses is expected to generate unique information about the complex
processes regulating epileptogenesis. The innovative strategy using RISC association as a surrogate for
microRNA function, and association of mRNAs with the RISC or actively translating ribosomes as a surrogate
for their silencing or translation, respectively, is expected to provide an improved functional assessment of the
silencing activity of microRNAs and the effect on target mRNAs compared to previous expression analyses. This
study will fill a crucial gap in the understanding of RISC function, protein expression and ...

## Key facts

- **NIH application ID:** 10225865
- **Project number:** 3R01NS107453-02S1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Christina Gross
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $124,901
- **Award type:** 3
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225865

## Citation

> US National Institutes of Health, RePORTER application 10225865, Functional analysis of the microRNA-induced silencing complex in epilepsy (3R01NS107453-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10225865. Licensed CC0.

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