# Mechanisms of microRNA dysregulation in Fragile X Syndrome

> **NIH NIH F32** · EMORY UNIVERSITY · 2023 · $69,500

## Abstract

PROJECT SUMMARY: Fragile X Syndrome (FXS) is the most common form of both inherited intellectual
disability and monogenic cause of autism. It is caused by the loss of Fragile X Messenger Ribonucleoprotein 1
(FMR1/FMRP) protein. FMRP, an RNA-binding protein, regulates target mRNAs through a variety of modes,
such as controlling mRNA localization, stabilization, editing, and/or translation. Translational repression by
FMRP is especially important in neuronal processes, where protein synthesis must be controlled in an orderly
fashion. In the absence of FMRP, translational control is disrupted resulting in the over-production of dendritic
proteins contributing to the FXS neuron phenotype of immature spines and hyperexcitability. Proper translation
regulation by FMRP requires microRNAs (miRNAs) and the RNA-induced silencing complex {RISC). The RISC
regulates gene expression post-transcriptionally by utilizing base matching between a miRNA and target mRNA,
which allows for specific recognition of target mRNAs. It has been shown that miRNAs are dysregulated in
several FXS models; however, no study has unbiasedly characterized the complete mi RNA landscape in human
FXS models. Another unaddressed aspect of FMRP-miRNA mediated gene regulation is whether the interactions
are always cooperative. Recent studies have highlighted an underappreciated role for FMRP in enhancing
translation rather than suppressing it. Thus, I hypothesize that FMRP loss alters the miRNA landscape, and that
FMRP not only coordinates miRNA-mediated repression, but in some cases antagonizes the miRNA-RISC
machinery to protect transcripts from improper regulation. To test my hypotheses, I will conduct experiments
aimed at the following goals: 1.) Test whether loss of FMRP alters global neuron miRNA expression patterns,
miRNA incorporation into the RISC, and localization of miRNAs to neuronal processes. 2.) Determine whether
FMRP-microRNA interactions regulate global and/or local translation of FMRP target mRNAs. To accomplish
these aims, I will require new training in induced-pluripotent stem cell cultures, neural organoids, and microscopy.
My sponsor, Dr. Gary Bassell, has expertise in these methods, and the scientific community of Emory University
School of Medicine will offer me an excellent training environment. Successful completion of this fellowship
proposal will not only reveal the extent to which miRNAs are dysregulated in human models of FXS, but also
reveal whether FMRP and miRNAs always act in a unimodal manner. Of equal importance, this project coupled
with Dr. Bassell's mentorship will allow me to transition from a molecular cancer biologist to an independent
molecular and cellular neurobiologist.

## Key facts

- **NIH application ID:** 10825482
- **Project number:** 1F32MH135636-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Adam Kosti
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $69,500
- **Award type:** 1
- **Project period:** 2023-09-13 → 2026-09-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825482

## Citation

> US National Institutes of Health, RePORTER application 10825482, Mechanisms of microRNA dysregulation in Fragile X Syndrome (1F32MH135636-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10825482. Licensed CC0.

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