# Investigating the Translatome in Genetic Models of Autism

> **NIH NIH R21** · YALE UNIVERSITY · 2024 · $208,342

## Abstract

PROJECT SUMMARY
There is an urgent need to gain a greater understanding of basic biological mechanisms in autism spectrum
disorders (ASDs) as a path to discover new therapeutic targets. In this proposal, we aim to leverage cutting-
edge genomic technologies together with the unique advantages of zebrafish to investigate the effect of loss of
function of two top ASD risk genes, CHD8 and SCN2A, on translation regulation in the developing brain. Our
central goal is to elucidate the mechanisms by which loss of function of these genes affects translation
in both neurons and glia, predisposing to cell type-specific deficits. Our central hypothesis is that ASD
gene disruption will lead to alterations in the global translatome in the developing vertebrate brain, predisposing
to cell type-specific abnormalities. This hypothesis is based on our compelling preliminary data demonstrating
that translation is a significantly dysregulated pathway in whole-brain RNA-seq of zebrafish mutants of three top
ASD risk genes, all of which display robust behavioral, brain structural and activity phenotypes. To test this
hypothesis, we will perform Translating Ribosome Affinity Purification sequencing (TRAP-seq) using a novel
zebrafish Ribo-Tag transgenic line to evaluate actively translated mRNAs in neurons and glia derived from whole
brains of zebrafish mutants of chd8 and scn1lab (Aim 1), and single cell RNA-seq (scRNA-seq) to characterize
cell type-specific differences in mutants (Aim 2). We expect that our highly innovative and exploratory approach
will provide new insights into how two top ASD risk genes affect translation regulation and cell type composition
in the developing vertebrate brain. The expected outcome of this research is to advance our understanding of
translation as a central regulatory mechanisms underlying ASDs. This research will advance the field by
illuminating a novel targetable pathway downstream of ASD genes with potential therapeutic implications.

## Key facts

- **NIH application ID:** 10824339
- **Project number:** 5R21MH133245-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** ELLEN J HOFFMAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $208,342
- **Award type:** 5
- **Project period:** 2023-04-15 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824339

## Citation

> US National Institutes of Health, RePORTER application 10824339, Investigating the Translatome in Genetic Models of Autism (5R21MH133245-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10824339. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*