# Synthetic biology for the chemogenetic manipulation of pain pathways

> **NIH NIH R21** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $231,643

## Abstract

Project Summary
The methods of synthetic biology have transformed practice throughout the biological sciences, but have yet to
find wide application in neurobiology. This is in part because many signaling receptors and pathways in the
brains are shared, limiting the latitude for narrowly targeted engineering strategies. To create a wider range of
tools for selective cell modulation, we propose to develop directed evolution methods that will generate
orthogonal neural receptors that respond to cannabinoids and offer multiple different chemogenetic control points
across the brain and thereby open the way to a synthetic neurobiology. The proposed methods should yield very
High Affinity receptors, that have Validated Orthogonalities for their receptor:ligand Couples. Our HAVOCs will
stand in contrast to current DREADD and DART approaches in that they will allow the use of natural effectors,
but at much lower concentrations, in essence flying below the ‘radar cover’ of endogenous receptors in the brain.
In particular, we will use HAVOCs to examine the gate theory of pain, and in consequence serve as a surrogate
model for targeted nano-dosing strategies for cannabinoids to safely promote analgesia and combat addiction.
As a starting point for the development of nano-dosing strategies, we will focus on the CB2 receptor, which is
sparsely expressed in the brain, but which has known functions in inhibiting dopaminergic neurons. Using our
novel directed evolution method, Compartmentalized Partnered Replication (CPR), we will initially evolve
individual variants of CB2 that can interact with high affinity with the cannabinoids b-caryophyllene, cannabidiol
(CBD), and other minor cannabinoids (Aim 1). We will proof the utility of these compounds and their evolved
receptors with isolated neurons and directly in a mouse model for pain (Aim 2). While movement to the clinic will
ultimately require introduction of novel receptors into patients, likely via gene therapies, the ability to target
protein production in particular neural pathways may provide one of the few viable methods for the chronic
treatment of pain. Into the future, the directed evolution strategies we have developed are fungible between
multiple different receptors and receptor types, and we suggest that HAVOCs may therefore serve as
generalizable neurotechnological tools to understand and manipulate a variety of neural functions.

## Key facts

- **NIH application ID:** 10017883
- **Project number:** 5R21AT010777-02
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Andrew D Ellington
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $231,643
- **Award type:** 5
- **Project period:** 2019-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017883

## Citation

> US National Institutes of Health, RePORTER application 10017883, Synthetic biology for the chemogenetic manipulation of pain pathways (5R21AT010777-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10017883. Licensed CC0.

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