# AGE-DEPENDENT MECHANISMS OF METABOLIC RECOVERY IN HEMORRHAGIC SHOCK

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $333,900

## Abstract

Project Summary
Multiple organ dysfunction syndrome (MODS), consequent to trauma, is a major underlying cause of mortality in
intensive care units. Research supported by the previous funding cycle has revealed fundamental mechanisms
that modulate inflammation and metabolic recovery during MODS through activation of the AMP-activated
protein kinase (AMPK), a central regulator of cellular energy homeostasis and mitochondrial quality control. This
work has now logically progressed to investigating the molecular machinery that is initiated by humanin, a
mitochondrial derived peptide with putative cytoprotective properties in aging. By using a clinically relevant
murine model of hemorrhagic shock, we have observed that changes in plasma humanin levels correlate with
AMPK failure and severity of organ injury in mature and old, but not young mice. Furthermore, administration of
the potent humanin analogues, humanin-G (HNG) and colivelin, afforded beneficial effects in an AMPK-
dependent and -independent manner, also involving the signal transducer and activator of transcription 3
(STAT3). The present proposal seeks to understand how humanin participates in these signaling pathways to
improve mitochondrial function and promote organ metabolic recovery. We will conduct a multidisciplinary
investigation to dissect these cross-talks by employing both genetic and pharmacological approaches of loss-of-
function of AMPK and STAT3, and by using humanin analogues in model systems of in vivo integrated physiology
combining molecular profiles and functional measurements. A special consideration will be given to the biological
variables of age and sex that are known to affect progress of organ injury and outcomes in critically ill patients.
Specifically, we will determine whether: 1) the spatio-temporal kinetics of humanin during hemorrhagic shock
correlate with MODS; 2) humanin has a biological role in modulating the pathophysiology of MODS; 3) humanin
contributes to the regulation of mitochondrial function by AMPK-independent metabolic pathways or AMPK-
independent signaling through modulation of STAT3 subcellular localization and activation. The successful
completion of this work will reveal fundamental stress-responsive circuits of mitochondrial quality control and
identify new therapeutic targets that can have a major impact in clinical intervention.

## Key facts

- **NIH application ID:** 10449367
- **Project number:** 5R01GM115973-08
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** BASILIA ZINGARELLI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $333,900
- **Award type:** 5
- **Project period:** 2015-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449367

## Citation

> US National Institutes of Health, RePORTER application 10449367, AGE-DEPENDENT MECHANISMS OF METABOLIC RECOVERY IN HEMORRHAGIC SHOCK (5R01GM115973-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10449367. Licensed CC0.

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