# Unlocking evolutionarily latent immune functions for treating disease

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $1,148,267

## Abstract

Project Summary/Abstract
All animals possess a robust innate immune response that depends on their ability to recognize viral double-
stranded RNA (dsRNA) as foreign. Yet, animal cells also encode and express dsRNA, and this cellular dsRNA
must be distinguished as “self” to prevent an aberrant immune response. Adenosine deaminases that act on
RNA, or ADARs, deaminate dsRNA to mark it as self and prevent an aberrant immune response. In this capacity
ADARs serve as an ”Innate Immune Checkpoint” (IIC), and recent studies reveal that a decrease in ADAR activity
in tumors releases this IIC, eliciting an immune response that leads to cell death. ADARs are the only IIC known
to date, and proposed studies are designed to fill this gap in knowledge towards the goal of new
immunotherapies. Comparative phylogenetic analyses will be complemented with molecular biology and
biochemistry experiments to identify mitigators, such as ADARs, that prevent inappropriate deployment of
antiviral defense, and ancient incompatibilities, such as invertebrate proteins that may activate an antiviral
response when introduced into vertebrates. Experiments in mammalian cells and mice, and the invertebrate
model organism, C. elegans, will provide a wide phylogenetic sampling to identify, test, and compare new IICs.
Engineered mice and cell lines are in hand, and established assays are in place, to monitor effects on the immune
pathway of both animals. Known dsRNA binding proteins, as well as those identified by immunoprecipitation
strategies, will be prioritized by phylogenetic assays for testing as IICs. In vitro biochemistry experiments, and
structural analyses, will guide subsequent rounds of phylogenetic comparisons. Mammalian ADAR1 p150
prevents an interferon response by modulating the MDA5 arm of the vertebrate innate immune pathway, and
IICs for the RIG-I arm have not been reported. Strategies to identify IICs for the RIG-I arm will focus on enzymes
known to modify the 5' terminus of RNA, a known epitope for RIG-I recognition. The culmination of proposed
studies will be the evaluation of candidate IICs in experimental models of tumorigenesis.

## Key facts

- **NIH application ID:** 10240664
- **Project number:** 5R01CA260414-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Brenda L. Bass
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,148,267
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240664

## Citation

> US National Institutes of Health, RePORTER application 10240664, Unlocking evolutionarily latent immune functions for treating disease (5R01CA260414-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10240664. Licensed CC0.

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