# LRRC57 modulates neurotrophic growth factor signaling in synaptic function and behavior

> **NIH NIH R21** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $500,500

## Abstract

Abstract
Our understanding of the biology of neuropsychiatric disease is still in the early stages. Genome-wide association
studies have identified multiple genomic loci associated with such diseases, but the biology of many of those
targets is still unknown. In this proposal, we focus on the LRRC57 gene, which was identified among the top
targets for bipolar disorder, a devastating psychiatric condition that affects millions of people around the world
and is characterized by extreme mood swings, ranging from mania to depressive episodes, each of which can
last for several days. The Lrrc57 gene encodes a 27-kDa horseshoe-shaped protein that belongs to the Leucine-
Rich Repeat domain–Containing proteins and is evolutionarily conserved. LRRC57 is expressed in neurons, and
its germline deletion is lethal in flies and worms. Despite its importance, no studies on the biology of LRRC57
have been reported in the literature. Our preliminary data show that germline Lrrc57 deletion is also lethal in
mice. Furthermore, we determined that the LRRC57 protein mediates the function of neurotrophic growth factors,
which are important for neural development, synaptic plasticity, and cognition. In preparation of this proposal, we
have produced a specific monoclonal anti-LRRC57 antibody and genetically engineered mice with global Lrrc57
deletion, mice with the conditional deletion of Lrrc57 in neurons only, and mice with the conditional
overexpression of Lrrc57 in neurons at different developmental stages. Using these tools, we propose to
elucidate the biochemical functions of LRRC57 by identifying its interacting protein partners, determining the
functional importance of those interactions, and establishing the molecular profile of the mouse brain upon Lrrc57
deletion or overexpression (Aim 1). We also propose to investigate the role of LRRC57 in neural excitability,
synaptic transmission, and long-term synaptic plasticity, with a focus on neurotrophin-dependent forms of
synaptic plasticity in the hippocampus (Aim 2). In this Aim, we will also test cognitive function and bipolar
disorder–related behaviors in mice with conditionally deleted or overexpressed Lrrc57. This work will establish
the foundation for gaining an understanding of the biology of the previously unrecognized, evolutionarily
conserved Lrrc57 gene and potentially reveal its involvement in bipolar disorder.

## Key facts

- **NIH application ID:** 10952389
- **Project number:** 1R21MH138869-01
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Stanislav S Zakharenko
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $500,500
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10952389

## Citation

> US National Institutes of Health, RePORTER application 10952389, LRRC57 modulates neurotrophic growth factor signaling in synaptic function and behavior (1R21MH138869-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10952389. Licensed CC0.

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