# A novel protective mechanism in hemorrhagic shock

> **NIH NIH R01** · RHODE ISLAND HOSPITAL · 2021 · $411,450

## Abstract

Hemorrhagic shock in a major cause of death and disability both in the United State and globally. Patients who
survive the initial hemorrhage and trauma insult have poor functional outcomes and significantly increased long
term mortality. The management of rapid hemorrhage control is critical for improving survival in
shocked patient in surgery. Notably, systemic insulin resistance and metabolic disorders manifested as one of
the most common pathological processes in trauma and hemorrhage. The intervention for suppressing insulin
resistance and metabolic stress remarkably reduced the mortality of trauma and hemorrhage patients. Thus, the
strategy for controlling metabolic disturbances in hemorrhage and trauma has been recognized as one of the
most promising therapies in surgery. Skeletal muscle serves as an important secretory organ that secrete
numerous myokines, which have crucial roles in countering insulin resistance and metabolic disorders. Irisin, a
newly identified hormone, cleaved from Fibronectin type III domain containing 5 (FNDC5), is restrictedly secreted
from the skeletal muscle resource to regulate insulin sensitivity. Notably, the irisin receptor integrin V5 (IRRIV)
was recently identified to couple with irisin for eliciting a signaling pathway. Our exciting discovery has identified
irisin as having a key role in improving insulin sensitivity in skeletal cells via AMPK pathway. We have found that
hemorrhage resulted in a marked decrease in irisin and irisin receptor in skeletal muscle. Furthermore, a
profound impairment in systemic insulin resistance in hemorrhage was remarkably mitigated by irisin. Strikingly,
the deletion of irisin using CRISPR/Cas9 genome editing technology in vivo induced a profound insulin resistance
in the whole body. By using newly developed CRISPR/Cas9 genome editing technology, non-viral Gold-
nanoparticle delivery system, high throughput next generation sequencing, and large-scale assay of cytokines,
we will test our central hypothesis that irisin coupling with irisin receptor contributes critically to modulating insulin
resistance in hemorrhage at the genetic, cellular, and whole body levels. The proposed studies will be performed
based on the three specific aims. Specific Aim #1: Determine irisin/irisin receptor IRRIV modulation and their
impact on mitochondrial function in response to hemorrhage and trauma. Specific Aim #2: Determine the
functional role of irisin and irisin receptor in modulating systemic insulin resistance and metabolic disorder in
hemorrhage. Specific Aim #3: Determine whether irisin and irisin receptor IRRIV mediate hemorrhage-induced
cardiac depression, inflammatory cytokines and ultrastructural damage. Taken together, the proposed studies
will for the first time define the crucial function of the irisin/irisin receptor in mediating insulin resistance and
metabolic disorders in hemorrhage. The proposal uncovers novel insight into understanding the mechanism of
hemorrhage in the f...

## Key facts

- **NIH application ID:** 10185587
- **Project number:** 1R01GM141339-01
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** TING C ZHao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $411,450
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10185587

## Citation

> US National Institutes of Health, RePORTER application 10185587, A novel protective mechanism in hemorrhagic shock (1R01GM141339-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10185587. Licensed CC0.

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