# Vesicular trafficking mechanisms regulating granulocyte function

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $434,000

## Abstract

Project Summary: Intracellular vesicular transport is essential for all aspects of neutrophil physiology and
defects in this mechanism leads to disease in humans. In neutrophils, vesicular trafficking is associated with the
processes of exocytosis, phagocytosis, signaling and transmigration; however, the molecular mechanisms that
regulate mobilization of the different neutrophil secretory organelles require further elucidation. We have
identified several key regulators of neutrophil granule trafficking, including the small GTPase Rab27a and its
effectors JFC1 and Munc13-4. We have also identified WASH as a neutrophil factor that regulates cytoskeleton
remodeling, vesicular trafficking and exocytosis. Furthermore, we have pioneered the development of systems
biology approaches to analyze vesicular dynamics and actin remodeling in granulocytes. Finally, we have
identified a novel mechanism of late endosomal maturation that involves the interaction between the calcium
sensor Munc13-4 and the late endosomal SNARE protein syntaxin 7 (STX7), to regulate TLR9 signaling and
downstream neutrophil functions. Here, we use innovative quantitative methods to elucidate the mechanisms
regulating vesicular transport associated with exocytosis, phagocytosis and late endosomal maturation in
neutrophils. We also propose to use novel small-molecule inhibitors of Rab27a-JFC1 and Munc13-4-STX7
binding to investigate mechanisms of vesicular transport and to elucidate neutrophil function in disease using in
vivo models of systemic inflammation. The central goal of this grant is to elucidate the vesicular transport
mechanisms that govern neutrophil pro-inflammatory processes, develop translational approaches to interfere
with these processes and provide preclinical validation for their use to attenuate systemic inflammation. Since
dysregulated neutrophil activation is injurious to the host and neutrophil secretory proteins play fundamental
roles in the damage to the endothelium associated with endotoxemia, sepsis and sterile inflammation, these
studies have important physiological significance and potential clinical applications. We hypothesize that the
differential regulation of vesicular transport by Rab27a and its effectors is an essential mechanism to determine
specific neutrophil functions and responses to insult. We also propose that small-molecule modulators of specific
vesicular transport pathways will prevent some of the deleterious consequences of neutrophil activation during
systemic inflammation. To test our hypotheses we propose the following Specific Aims: 1) Define the
mechanisms that differentially regulate vesicular trafficking, actin-dependent propulsion and blockage, and
exocytosis of neutrophil granule subsets; 2) Establish the molecular mechanisms regulating endosomal
maturation, endosomal function and nucleic acid-sensing TLR-signaling in neutrophils; 3) Develop mechanistic
and translational approaches to regulate neutrophil vesicular trafficking pa...

## Key facts

- **NIH application ID:** 10225236
- **Project number:** 3R01HL088256-11S1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Sergio Daniel Catz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $434,000
- **Award type:** 3
- **Project period:** 2008-12-03 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225236

## Citation

> US National Institutes of Health, RePORTER application 10225236, Vesicular trafficking mechanisms regulating granulocyte function (3R01HL088256-11S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10225236. Licensed CC0.

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