# FMRP-mediated Regulation in Human Brain Development and Therapeutic Advancement

> **NIH NIH P50** · EMORY UNIVERSITY · 2021 · $1,600,000

## Abstract

Project Summary
Fragile X syndrome (FXS) is an X-linked disorder of intellectual disability (ID) that is most commonly due to the
expansion of a CGG-repeat in the 5’-untranslated region of the FMR1 gene. CGG expansion beyond 200 repeats
leads to hypermethylation of the FMR1 promoter, resulting in the loss of FMR1 expression. FXS is thereby
caused by the loss of functional fragile X mental retardation protein (FMRP). Over the course of nearly three
decades of research since the discovery of the FMR1 gene, much has been learned about the function of FMRP
and the consequence of its absence, primarily using mouse and fruit fly model systems. FMRP is a selective
RNA-binding protein associated with messenger ribonucleoprotein mRNPs and/or stalled polyribosomes that
appears to be involved in the regulation of local protein synthesis at synapses. The loss of FMRP leads to
dysregulated translation of selective mRNAs. Substantial progress in characterizing the underlying disease
mechanisms in animal models has led to highly successful preclinical studies of drugs modulating metabotropic
glutamate and GABA receptors. However, follow-up clinical trials in humans have been largely unsuccessful,
highlighting the imprecision of using the mouse model of FXS. Development of human iPSCs-derived monolayer
culture (2D) and three-dimensional (3D) organoid culture systems, which recapitulate key features of human
brain development, have provided a platform to model human development and disease, as well as to better
screen for therapeutic drugs. Little is known of FMRP-mediated regulation of human brain development or the
extent of its plasticity, which is essential to fully understand the pathophysiology of FXS. The overarching goal
of this Center is to take a systematic approach to investigate how FMRP may regulate human brain development
and circuit functions, and develop novel therapeutic approaches to treat FXS. Using our established human 2D
and 3D model systems as well as mouse models, we will determine the role of FMRP in human brain function
and systematically identify the functional mRNA targets of FMRP in human brain development and circuit
functions. We will also use these iPSC models as translational tools to develop novel therapeutic approaches
for FXS. The Center brings together an outstanding team of investigators with expertise in transcriptomic
analyses, genome-wide translation profiling (translatomes), FMRP-RNA interactomes, single cell genomics, cell
type-specific manipulations, dissection of activity- and circuit-dependent mechanisms, and high-throughput small
molecule screening. Our coordinated effort will create scientific synergy and significantly advance our
understanding of FMRP-mediated gene regulation in human brain development and circuit functions and enable
novel therapeutic development for fragile X syndrome.

## Key facts

- **NIH application ID:** 10271305
- **Project number:** 5P50HD104458-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** PENG JIN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,600,000
- **Award type:** 5
- **Project period:** 2020-09-25 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271305

## Citation

> US National Institutes of Health, RePORTER application 10271305, FMRP-mediated Regulation in Human Brain Development and Therapeutic Advancement (5P50HD104458-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10271305. Licensed CC0.

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