# Metabolic alterations in hemorrhagic shock

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2020 · $292,600

## Abstract

Project Summary
Hemorrhagic injury (HI) is a leading cause of death in people under the age of 45 and accounts for
almost half of trauma-related deaths. Hemorrhagic shock leads to whole body hypoxia, nutrient
deprivation and dysregulation of critical biochemical pathways that may result in multiple organ
dysfunction syndrome and death. Mitochondrial functional decline is a hallmark of hemorrhagic
shock and enhanced mitochondrial function is known to contribute to better outcome following HI in
animal models.. Our goal is to reduce the incidence of death due to HI and shock by identifying
endogenous mechanisms that modulate metabolic homeostasis following HI. Our central
hypothesis is that AMPK-SIRT1 axis modulate mitochondrial function following Hemorrhagic injury.
Our objectives are to 1) use genetically modified mice and both small molecule activators and
inhibitors of critical proteins involved in metabolic pathways linked to mitochondrial function so that
specific targets can be identified to treat HI and other low flow conditions; 2) determine the roles of
PDE-AMPK-mediated regulation and direct SIRT1 regulation in mitochondrial functional modulation
following HI; 3) Identify mechanism by which niacin modulates SIRT1 activity and mitochondrial
function following HI; 4) identify methods to improve mitochondrial function by determining critical
metabolic pathways that regulate cellular energetics, and 5) develop novel therapeutic strategies to
reduce the metabolic imbalance following HI. Aim 1 tests the hypothesis that AMPK-SIRT1 axis is
critical in improving mitochondrial function and survival following HI. We will determine the role of
the PDE-AMPK pathway and direct SIRT1 regulation in HI. We will determine the molecular
players in these pathways by testing key metabolic measures such as NAD/NADH ratio, p-AMPK,
CaMKK and Pgc-1 following HI, and after treatment with agents that activate or inhibit key
proteins involved in these pathways. Aim 2 tests the hypothesis that niacin improves survival after
HI by augmenting intracellular NAD+. We propose to identify the metabolic check points in HI and
new therapeutic strategies to prolong life. The proposed research is relevant to that part of NIH’s
mission that pertains to developing fundamental knowledge that will potentially help to reduce the
burdens of human disease. The outcome of this research will be significant because the
fundamental knowledge gained from this study is expected to advance methods to promote healthy
living.

## Key facts

- **NIH application ID:** 9906904
- **Project number:** 5R01GM122059-04
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Raghavan Pillai Raju
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $292,600
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906904

## Citation

> US National Institutes of Health, RePORTER application 9906904, Metabolic alterations in hemorrhagic shock (5R01GM122059-04). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9906904. Licensed CC0.

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