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.

Public Health Relevance

Our goal is to reduce the incidence of death due to hemorrhagic injury and shock by identifying endogenous mechanisms that modulate metabolic homeostasis following Hemorrhagic injury. Our expected outcomes include 1) improved understanding of metabolic regulation mediated by AMPK activation and modulation of SIRT1; 2) identification of the differential role of niacin receptor and NAD+ in hemorrhagic injury, 3) identification of targets and methods to improve mitochondrial function by determining critical metabolic mediators that regulate cellular energetics and 4) identification of therapeutic strategies to reduce the metabolic imbalance following injury which are based on key mediators and mechanisms identified by this project. Our impact include 1) improved understanding of metabolic perturbations and mitochondrial functional changes in hemorrhagic injury, and 2) identification of newer targets to develop better therapeutics in Hemorrhagic injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM122059-03
Application #
9689038
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Zhao, Xiaoli
Project Start
2017-08-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Augusta University
Department
Radiation-Diagnostic/Oncology
Type
Sch Allied Health Professions
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Warren, Marie; Subramani, Kumar; Schwartz, Richard et al. (2017) Mitochondrial dysfunction in rat splenocytes following hemorrhagic shock. Biochim Biophys Acta Mol Basis Dis 1863:2526-2533
Raju, Raghavan (2017) Immune and metabolic alterations following trauma and sepsis - An overview. Biochim Biophys Acta Mol Basis Dis 1863:2523-2525