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Principal Investigator: Frederic Tremaine Billings
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $432,500
Funding agency: National Institute of General Medical Sciences
Project Summary/Abstract
More than 20% of patients undergoing major surgery experience acute kidney, brain, and heart injury,
and these perioperative complications lead to persistent organ dysfunction, long-term morbidity, and death. My
research program is investigating and manipulating mechanisms of perioperative organ injury in order to
identify therapeutic targets and develop novel therapies. We are currently focused on the critical impact of
oxygen tension on organ injury, because perioperative oxygen administration is inconsistent, unguided, often
excessive, and potentially harmful. Both hypoxia and hyperoxia can be harmful to surgical patients, yet both
occur frequently, despite the ease with which the fraction of inspired oxygen (FiO2) can be manipulated in the
perioperative period. Our laboratory is focused on identifying and investigating molecular pathways and
therapeutic targets that a) impact oxygen tension in tissues during surgery and b) impact hypoxia- and
hyperoxia-mediated organ injury. We target these molecular pathways to reduce organ injury.
We have recently demonstrated that: 1) perioperative oxidative damage increases acute kidney, brain,
and heart injury; 2) intraoperative normoxia improves vascular reactivity compared to hyperoxia possibly by
reducing intraoperative oxidation of the heme moiety of vascular smooth muscle soluble guanylyl cyclase; 3)
normoxia upregulates hypoxia inducible factor (HIF)-regulated transcription and reduces circulating markers of
oxidative damage; and 4) increased circulating cell-free hemoglobin (Hb) oxidizes lipids and is independently
associated with postoperative kidney, lung, and brain injury. In the next 5 years we will investigate the effects
of oxygen tension on mechanisms of organ injury, including oxidative damage, vascular function, HIF signaling,
and cell free Hb-mediated organ injury, using a multifaceted translational approach. Our program combines
laboratory experiments in human tissues and preclinical models with prospective cohort studies and
mechanistic trials in patients having major surgery. We perform experiments on arterioles and arteries isolated
from patients during surgery to study the effects of hypoxic, normoxic, and hyperoxic treatments on vascular
function. We investigate the impact of oxygen treatments during preclinical models of acute kidney injury in
genetically engineered mice in collaboration with oxygen biologist nephrologist Volker Haase, and we are
measuring the effect of intraoperative hyperoxia vs. normoxia treatment in samples biobanked from the
NIGMS-supported ROCS clinical trial. Examples of these experiments include the measurement of HIF-
regulated transcripts in atrial myocardium and the oxidation state of the heme group in plasma cell-free Hb. We
will complement these hypothesis-driven experiments with unbiased approaches to measure the transcriptome
and protein responses in vascular and murine tissues to identify and support new paths of investigation.
This rigorous multimodal strategy provides the framework to advance the understanding of perioperative
organ injury and guide the development of therapies for hundreds of thousands of surgical patients.
Terms: <Acquired brain injury><Acute Renal Failure with Renal Papillary Necrosis><Arteries><Atrial><Blood Plasma Cell><Blood Vessels><Body Tissues><Brain Injuries><Cardiac Atrium><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Clinical Trials><Collaborations><Complement><Complement Proteins><Death><Dysfunction><Ferroprotoporphyrin><Functional disorder><GEM model><GEMM model><GUCY><Gene Transcription><Genetic Transcription><Genetically Engineered Mouse><Heart Atrium><Heart Injuries><Heme><Heme Group><Hemoglobin><High Prevalence><Hyperoxia><Hypoxia><Hypoxia Inducible Factor><Hypoxic><Injury to Kidney><Intracellular Communication and Signaling><Investigation><Laboratories><Lead><Lung damage><Measurement><Measures><Mediating><Mice><Mice Mammals><Molecular><Molecular Target><Morbidity><Morbidity - disease rate><Murine><Mus><Myocardium><NIGMS><National Institute of General Medical Sciences><O element><O2 element><Operative Procedures><Operative Surgical Procedures><Organ><Oxygen><Oxygen Deficiency><Oxygen Inhalation Therapy><Oxygen Therapy Care><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pb element><Perioperative><Perioperative complication><Physiopathology><Plasma Cells><Plasmacytes><Post-Operative><Postoperative><Postoperative Period><Pre-Clinical Model><Preclinical Models><Prospective, cohort study><Proteins><Protoheme><RNA Expression><Research><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Soluble Guanylate Cyclase><Soluble Guanylyl Cyclase><Surgical><Surgical Interventions><Surgical Procedure><Tissue Model><Tissues><Transcript><Transcription><Vascular Smooth Muscle><Warburg Therapy><acute kidney injury><arteriole><atrium><biobank><biological signal transduction><biorepository><brain damage><brain-injured><cardiac injury><cardiac muscle><circulating biomarkers><circulating markers><complementation><develop therapy><experience><experiment><experimental research><experimental study><experiments><ferroheme><genetically engineered mouse model><genetically engineered murine model><global gene expression><global transcription profile><heart muscle><heavy metal Pb><heavy metal lead><human tissue><hyperoxygenation><improved><injury to organs><intervention development><kidney injury><lab assignment><lab experiment><laboratory activity><laboratory assignment><laboratory exercise><laboratory experiment><lung injury><multi-modality><multimodality><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><nitric oxide receptor><nitric oxide-sensitive guanylyl cyclase><normoxia><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><organ injury><oxidation><oxidative damage><oxidative injury><oxidized lipid><oxygen administration><oxygen therapy><pathophysiology><pathway><patient oriented outcomes><plasmocyte><programs><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><renal injury><response><sGC protein><surgery><therapeutic target><therapy development><transcriptome><translation strategy><translational approach><translational strategy><treatment development><vascular>