# Functional characterization of understudied protein kinases implicated in developmental disorders using zebrafish

> **NIH NIH R03** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2021 · $174,800

## Abstract

Summary
About 3000 protein-coding genes in the human genome encode druggable proteins that can bind to small
molecules. Most of these “druggable genes” encode proteins that belong to just three protein families: protein
kinases, non-olfactory G-protein-coupled receptors (GPCRs), and ion channels. Drug discovery projects have
focused on well-studied proteins from these families. As a consequence, FDA-approved drugs target only a
fraction of these ~3000 druggable genes. There is an urgent need to fill this gap and inform novel therapeutic
strategies for human disease. To meet this need, the NIH’s Illuminating Druggable Genome (IDG) program has
prioritized a list of over 300 understudied protein kinases, GPCRs, and ion channels. High throughput screens
in diverse cell types and model organisms are a mainstay of drug discovery. Zebrafish are amenable to high
throughput screening and, as vertebrates, can closely recapitulate the complexity of human development,
homeostasis, and disease. These advantages make zebrafish uniquely well suited to uncover clinically relevant
drugs. We and others have optimized the CRISPR/Cas9 mediated mutagenesis method to screen for
phenotypes in the F0 generation by generating biallelic mutations. This breakthrough accelerated our ability to
uncover the functional consequences of hundreds of mutants from months to days. Mutations in kinases can
lead to diverse dysfunctions in humans, including cancer, aberrant development, and metabolic disorders. We
analyzed 150 of the understudied kinase genes listed in RFA-RM-20-109 and identified 126 zebrafish orthologs.
Of these 126 genes, mutations in 21 are known to cause developmental disorders in humans. The objective of
this proposal is to establish zebrafish models for these 21 understudied genes that encode druggable kinases.
We will achieve our objective and test our hypothesis via the following aims: 1) Generate a Library of Zebrafish
Mutants Corresponding to 21 Candidate Developmental Disorder Genes. 2) Elucidate the functional
consequences of gene knockouts during embryonic development. We expect that 8-10 of the 21 druggable
genes will have early development phenotypes in zebrafish and generate disease models for further functional
studies. Our library will be useful not only for studying disease pathology but also for functional testing of kinase
inhibitors to elucidate their targets. Our mutant collection will facilitate drug screening to identify new therapeutics
for many human diseases and will be widely available through the Zebrafish International Resource Center
(ZIRC).

## Key facts

- **NIH application ID:** 10217780
- **Project number:** 1R03TR003694-01
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Gaurav K Varshney
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $174,800
- **Award type:** 1
- **Project period:** 2021-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217780

## Citation

> US National Institutes of Health, RePORTER application 10217780, Functional characterization of understudied protein kinases implicated in developmental disorders using zebrafish (1R03TR003694-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10217780. Licensed CC0.

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