# Regulation of synapse development by small GTPase cascades in Caenorhabditis elegans

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2024 · $390,600

## Abstract

Project Summary
Synaptic development is a highly conserved process that underlies the functional connectivity of the nervous
system. Deficits in synaptic development are associated with multiple neurological disorders, like autism
spectrum disorders, intellectual disabilities, epilepsy, and schizophrenia. Therefore, restoration of healthy
synapse development in cases of neurodevelopmental disorders represents one goal for developing better
treatments. However, the lack of molecular targets to achieve this goal presents a significant barrier to the
development of new therapies. Identifying the signaling pathways that promote or restore synapse development
will reveal new mechanisms for modulating neuronal circuit development and function. The overall goal for the
proposed research is to uncover how a series of small GTPases coordinate synapse development at the
Caenorhabditis elegans neuromuscular junction. The central hypothesis is that PXF-1, a Rap guanine nucleotide
exchange factor, promotes synapse development through the sequential activation of Rap, Ras, and Rac
GTPases to sustain perisynaptic actin filaments during neuromuscular development. To identify the molecular
mechanisms that govern the putative GTPase signaling cascade, we will use genetics and cell biology to identify
the guanine nucleotide exchange factors and GTPase activating proteins that modulate each GTPase in the
pathway. We will use fluorescent biosensors and genetic engineering to elucidate the molecular mechanisms
through which Rap, Ras, and Rac signaling pathways interact with one another. The proposed research is
innovative because it uses the powerful model system of Caenorhabditis elegans to study how GTPase networks
function as molecular switches to control synapse development and motor circuit function. The development and
use of new molecular tools to observe and modulate signal transduction in vivo will provide additional innovations
for cellular and molecular neuroscience. The studies proposed in this application are significant because they
will reveal how small G protein signaling networks promote synapse development and how modulation of these
GTPase signaling modules can mitigate neuronal circuit dysfunctions.

## Key facts

- **NIH application ID:** 10854831
- **Project number:** 5R01NS129668-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Salvatore James Cherra
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $390,600
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10854831

## Citation

> US National Institutes of Health, RePORTER application 10854831, Regulation of synapse development by small GTPase cascades in Caenorhabditis elegans (5R01NS129668-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10854831. Licensed CC0.

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