# Project 1

> **NIH NIH P50** · EMORY UNIVERSITY · 2021 · $536,706

## Abstract

Project Summary
Previous work in animal models of fragile X syndrome (FXS) has provided invaluable insight into the normal
molecular, cellular, and physiological functions of fragile X mental retardation protein (FMRP); however, an
effective treatment remains elusive. Although these failures could be attributed to several factors, it is now
apparent that it is imperative that FXS-associated phenotypes, the efficacy of drugs, and rescue strategies
characterized in animal models of FXS be validated and/or new phenotypes characterized in human FXS patient-
derived, disease-relevant cell types. A critical limitation is lack of an available human FXS patient-derived neural
model to investigate the role of FMRP-mediated regulation of protein synthesis and signaling. We have recently
developed multiple human iPSC-derived 2D neural and 3D cortical organoid models to investigate the role of
FMRP-mediated regulation of protein synthesis and signaling during brain development. The objectives of
Project 1 are to use these FXS patient iPSC-derived 2D monolayers as well as 3D cortical and hippocampal
organoids to address questions delineated in three specific aims. Aim 1 is to characterize protein synthesis
dysregulation and associated molecular, cellular and neurophysiological phenotypes in specific cell types across
neural development in human FXS iPSC neural models. Our preliminary data indicate that FXS patient cells
have increased protein synthesis rates, increased proliferation and altered migration, resulting in delayed
acquisition of cell fate and neuronal differentiation. These early neurodevelopmental defects are anticipated to
have consequences on neuronal development and function. Aim 2 is to identify FMRP targets and translationally
dysregulated mRNAs during brain development in multiple human FXS iPSC neural models. Using CLIP-seq we
have identified FMRP target mRNAs in both human cortical organoids and mouse embryonic cortex at similar
developmental stages. Our comparative analyses have revealed three groups of FMRP mRNA targets, human
only, mouse only and shared ones. We have also recently used ribosome profiling to identify translationally
dysregulated mRNAs, some of which are FMRP targets, in whole cortex in the adult mouse brain. Thus, ribosome
profiling will be applied to characterize the translatomes of FXS patients and controls using both isogenic
i3Neurons and i3Neurons from multiple patients, as well as from isogenic 3D cortical organoids. For comparison
between FXS models, we also will conduct ribosome profiling of FXS mouse embryonic cortex. In Aim 3, we will
devise targeted strategies to rescue cellular and synaptic phenotypes in human FXS iPSC neural models. We
will manipulate expression of dysregulated FMRP targets using lentivirus-based approaches to rescue FXS-
associated cellular and synaptic phenotypes. The outcome of the experiments in this Project, coupled with
synergy with the other projects, will uncover novel mechanisms an...

## Key facts

- **NIH application ID:** 10271307
- **Project number:** 5P50HD104458-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** GARY J BASSELL
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $536,706
- **Award type:** 5
- **Project period:** 2020-09-25 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271307

## Citation

> US National Institutes of Health, RePORTER application 10271307, Project 1 (5P50HD104458-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10271307. Licensed CC0.

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