# RNA silencing machinery in extracellular vesicle-mediated immunometabolic regulation

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $615,239

## Abstract

Project Summary
Obesity has solid inflammatory underpinnings, which are risk factors for various chronic inflammatory and
metabolic diseases such as type 2 diabetes (T2D). However, how obesity provokes aberrant inflammation
remains to be defined. Recent studies indicate that small extracellular vesicles (sEVs, a.k.a., exosomes)
carrying RNA, including microRNA (miRNA), play a critical role in inducing inflammation in obesity. In this
study, we aim to demonstrate that RNA silencing machinery plays a critical role in modulating RNA cargo
profiles in sEV-secreting cells and also in responding to exposure of RNA cargos of sEVs in sEV-receiving
cells. Our overarching goal is to reveal how RNA silencing machinery-mediated, sEV-induced events are
critical for controlling obesity-associated inflammation, impacting the development of chronic inflammatory
and metabolic diseases.
Small EVs are released from many cell types into the extracellular space and are distributed in body fluids.
These sEVs, taken up by neighboring and distant cells, subsequently modulate the functions of recipient cells.
Hence sEVs have emerged as important transducers of intercellular communication, with their cargos,
including miRNAs, playing critical roles in modulating sEV-recipient cellular activities. Our Preliminary data
show that circulating EVs from obese adolescents are enriched with specific RNA cargo and exhibit higher
pro-inflammatory traits, than those from lean subjects. Further, our newly established mouse model, which
enables us to monitor specific cell type-derived sEVs in vivo, indicates that in obesity, sEVs become pro-
inflammatory and when engulfed by macrophages, these pro-inflammatory sEVs induce inflammatory
responses in macrophages. These intriguing Preliminary data suggest novel mechanisms for EV-induced
inflammation in obesity.
Studies in this proposal will: (1) assess the role of RNA silencing machinery in sEV-secreting cells in
generating pro-inflammatory sEVs, and (2) evaluate the role of RNA silencing machinery in sEV-receiving
cells in mediating sEV-induced inflammation.
By utilizing our novel mouse models coupled with access to human samples and models, our systematic
approaches will reveal novel mechanisms of how the pathogenicity of sEVs is critical in the development of
inflammation in obesity-associated pathophysiology.

## Key facts

- **NIH application ID:** 10802795
- **Project number:** 1R01DK134646-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Takahisa Nakamura
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $615,239
- **Award type:** 1
- **Project period:** 2023-12-15 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10802795

## Citation

> US National Institutes of Health, RePORTER application 10802795, RNA silencing machinery in extracellular vesicle-mediated immunometabolic regulation (1R01DK134646-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10802795. Licensed CC0.

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