# RNA-programmable cell type targeting and manipulation across vertebrate nervous systems

> **NIH NIH UF1** · DUKE UNIVERSITY · 2021 · $586,344

## Abstract

Systematic experimental access to diverse neuronal cell types is a prerequisite to deciphering brain circuit
organization, function, and dysfunction. Thus fundamental progress in neuroscience urgently needs cell type
access technologies that are specific, comprehensive, easy to use, affordable, scalable, and general across
animal species. Most if not all current genetic approaches to cell type targeting are based on genome and
DNA engineering, which has inherent limitations in achieving the desired tool features. We have developed a
paradigm-shifting technology for cell type targeting and manipulation based on RNA engineering. This
technology builds upon the universal RNA sensing and editing system within metazoan cells, centered around
the enzyme adenosine deaminase acting on RNA (ADAR). We term this method CellREADR: Cell access
through RNA sensing by Endogenous ADAR. CellREADR can be deployed as a single RNA molecule that
detects specific cellular RNAs through Watson-Crick base pairing and switches on the translation of markers,
sensors, and effectors through a single base editing event; these RNA molecules can be delivered to animals
via viral expression vectors. As such, CellREADR is highly specific and comprehensive, fast, cheap, easy to
use, scalable, and in principle should apply to all animals. Importantly, CellREADR is inherently
programmable, with unprecedented versatility for combinatorial and multiplexed targeting and editing of cell
types in complex tissues. In this proposal, we will apply CellREADR to target and validate a large set of neuron
types of the broadly defined cerebral cortex and basal ganglia in several mammalian and avian species. Our
proposal is grounded on the evolutionary conservation as well as divergence of these forebrain cell types,
which may underlie conserved and divergent circuit function and behavior across species. We have
assembled an interdisciplinary team of investigators with expertise in molecular genetics, systems
neuroscience, human and clinical neuroscience, bioengineering, and computation genomics. First, we will
further optimize the CellREADR method and develop a comprehensive set of AAV tools for targeting and
manipulating all major transcriptomic types of glutamatergic (GLU) and GABAergic neurons of the mouse
cerebral cortex. Second, we will extend CellREADR to target and validate a large set of GLU and GABA
neuron types in human ex vivo cortical tissues, macaque monkey cerebral cortex, and zebra finch cortex and
basal ganglia. Third, we will establish a central CellREADR Portal for computational design of CellREADR
reagents across vertebrate species and dissemination of technology and resource throughout the
neuroscience community. By using cell-specific RNA profiles as the basis for genetic access and manipulation,
CellREADR cell-editing technology is poised to transform the scale and rate of discovery in neuroscience and
across biomedical fields. Impacts on the BRAIN Initiative will be immedi...

## Key facts

- **NIH application ID:** 10350096
- **Project number:** 1UF1MH128337-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Z JOSH HUANG
- **Activity code:** UF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $586,344
- **Award type:** 1
- **Project period:** 2021-09-13 → 2025-09-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10350096

## Citation

> US National Institutes of Health, RePORTER application 10350096, RNA-programmable cell type targeting and manipulation across vertebrate nervous systems (1UF1MH128337-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10350096. Licensed CC0.

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