# Designing synthetic transcription factors to study drug-specific transcription and behaviors

> **NIH NIH F31** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $24,464

## Abstract

PROJECT SUMMARY
The nucleus accumbens (NAc) is a key brain region which encodes responses to both natural and drug
reinforcers. All drugs of abuse are known to increase the dopaminergic tone in the NAc, making it a central brain
structure in coordinating drug response. Drugs of abuse act largely through synaptic targets to alter intracellular
signaling cascades which leads to the activation or inhibition of transcription factors, which in turn induce or
repress the expression of specific genes. These drug-induced functions of brain transcription factors are
sensitive to, and contribute to, the epigenetic landscape within a neuron and have been associated with lasting
alterations in neuronal function and drug-related behaviors. Therefore, understanding the drug-induced function
of transcription factors in this brain area may expand our understanding of how drugs of abuse can coordinate
lasting changes in drug-related behaviors. This knowledge is critical for the development of the next generation
of specific substance use disorder (SUD) medications. Here, I propose innovation centered on synthetic biology
approaches to re-program the function of transcription factors, for viral delivery in the brain of awake and
behaving mice, to resolve the exact, damaging transcription factor functions that are distinct to stimulant versus
opioid addiction. I propose to accomplish this by applying novel synthetic transcription factor constructs
combined with brain transcriptome profiling and drug self-administration procedures. This project focuses on
ZFP189, a novel drug-activated transcription factor that I have carefully characterized in my earlier graduate
work. First, in the NAc, I will virally deliver synthetic ZFP189 transcription factors, which possess artificial
functional moieties capable of exerting distinct forms of transcriptional control at all in vivo target genes. I will
perform RNA sequencing approaches to uncover how the complete gene-regulatory functions of a ZFP189 are
differentially engaged in the context of stimulant versus opioid use. Second, I will utilize these same synthetic
ZFP189 transcription factors to investigate their causal contributions to drug reinforcement using intravenous
drug self-administration procedures. By innovating the application of synthetic transcription factors that can be
programmed to exert novel forms of gene regulation across the genome, these techniques can be combined
with existing RNA sequencing and complex behavioral procedures to serve as tools for both molecular
interrogation into the transcription factor functions distinct to specific drugs of abuse and as highly specific
transcription manipulations to uncover the causal gene regulatory events that drive certain SUDs. Together, this
work will provide new approaches to identify the transcription factor functions at the core of specific SUDs and
yield refined gene candidates as targets for future SUD medications.

## Key facts

- **NIH application ID:** 10878750
- **Project number:** 5F31DA057830-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Joseph Anthony Picone
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $24,464
- **Award type:** 5
- **Project period:** 2023-06-25 → 2024-11-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878750

## Citation

> US National Institutes of Health, RePORTER application 10878750, Designing synthetic transcription factors to study drug-specific transcription and behaviors (5F31DA057830-02). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10878750. Licensed CC0.

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