Document text
Principal Investigator: Ethan John Anderson
Organization: UNIVERSITY OF IOWA
Fiscal Year: 2024
Award: $436,894
Funding agency: National Heart Lung and Blood Institute
ABSTRACT: Sepsis is a dangerous hyper-inflammatory condition that carries a mortality rate of 25% for
uncomplicated cases and rises to 80% for patients who develop multiple organ dysfunction syndrome (MODS).
No specific therapies for MODS exist, which is why identification of druggable targets and biomarkers for
diagnosis/prognosis are urgently needed. During the acute phase response in sepsis, circulating factors such
as cytokines and endotoxins cause oxidative stress and derangements in mitochondrial morphology and
function in the heart, ultimately leading to septic cardiomyopathy (SepCM), a manifestation of MODS.
Prohibitins (PHB1,2) are proteins that assemble in hetero-oligomeric complexes within the mitochondrial inner
membrane and in plasma membrane lipid rafts, where studies show they are at the nexus of many vital cellular
functions including metabolism, proliferation, oxidative stress and apoptosis. The current proposal stems from
our recent findings that PHB1 is a dynamic acute phase reactant protein in sepsis, and its secretion during
sepsis is abrogated in mice lacking the anti-inflammatory transcription factor Nrf2 (i.e., NFE2L2). Importantly,
bloodborne PHB1 is biologically active, as administration of recombinant human PHB1 (rPHB1) activates PI3K-
AKT signaling and enhances aerobic glucose oxidation and pentose phosphate pathway in the heart, and
preserves cardiac mitochondrial oxidative phosphorylation (OxPHOS) in mouse models of sepsis. We also
have very exciting preliminary evidence that serum PHB1 levels are associated with MODS and mortality in
sepsis patients. Experiments outlined in this proposal will test our central hypothesis that bloodborne PHB1 is a
stress-induced ‘hepatokine’ that mediates a liver-to-heart protective feedback signal during sepsis by
enhancing oxidative glucose metabolism (i.e. suppressing lactate production) and preserving mitochondrial
structure and function in the myocardium. This cardioprotective effect of circulating PHB1 can be
therapeutically exploited to treat SepCM.
Our established interdisciplinary team will test this hypothesis in three Aims. Work in Aim 1 will determine
the Nrf2-mediated mechanisms controlling PHB1 secretion in hepatocytes. In Aim 2 we will identify the
mechanisms of cardio-protection conferred by circulating PHB1 during sepsis. Work in Aim 3 will validate
serum PHB1 as a predictive biomarker of morbidity and mortality in a cohort of patients with established sepsis
(INVACS cohort, University of Utah). Each Aim is hypothesis-driven, and the work will be performed using
gain/loss-of-function approaches in primary cell culture, clinically relevant mouse models of severe sepsis, and
serum samples from a well-characterized cohort of sepsis patients. We will leverage the complementary and
uniquely distinct expertise of our research team to elucidate cardioprotective mechanisms of circulating PHB1,
and to exploit these mechanisms to treat a very serious and deadly clinical condition.
Terms: <1-Phosphatidylinositol 3-Kinase><21+ years old><AKT><Acute-Phase Proteins><Acute-Phase Reactants><Acute-Phase Reaction><Acute-Phase Response><Acute-Phase State><Adult><Adult Human><Aerobic><Akt protein><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Apoptosis><Apoptosis Pathway><BAP32 protein><Basal Transcription Factor><Basal transcription factor genes><Biological><Biological Markers><Biomedical Engineering><Blood><Blood Reticuloendothelial System><Blood Sample><Blood Serum><Blood specimen><Body Tissues><COVID-19><COVID-19 infection><COVID-19 virus infection><COVID19 infection><CV-19><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiomyopathies><Cell Communication and Signaling><Cell Function><Cell Line><Cell Membrane Lipid Rafts><Cell Physiology><Cell Process><Cell Signaling><Cell membrane><CellLine><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Characteristics><Clinical><Clinical Research><Clinical Study><Complex><Coronavirus Infectious Disease 2019><Culturing, in vitro Vertebrate, Primary><Custom><Cytoplasmic Membrane><D-Glucose><Dangerousness><Death><Death Rate><Dextrose><Diagnosis><Disease><Disorder><Drug Targeting><Dysfunction><ELISA><Endotoxins><Enzyme-Linked Immunosorbent Assay><Feedback><Functional disorder><Gene Modified><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Transcription><Glucose><Heart><Heart Muscle Cells><Heart failure><Heart myocyte><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Heterodimerization><Hexose Monophosphate Shunt><Human><Incubated><Infection><Inflammatory><Injury><Inner mitochondrial membrane><Intermediary Metabolism><Intracellular Communication and Signaling><KO mice><Knock-out Mice><Knockout Mice><Label><Ligands><Liver><Liver Cells><MOF syndrome><Manuscripts><Measures><Mediating><Membrane Microdomains><Metabolic Processes><Metabolic stress><Metabolism><Mice><Mice Mammals><Mitochondria><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Morphology><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Mus><Myocardial Diseases><Myocardial Disorder><Myocardial depression><Myocardial dysfunction><Myocardiopathies><Myocardium><Null Mouse><Organ><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Oxidative Stress><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><Pathway interactions><Patients><Pentose Phosphate Pathway><Pentose Phosphate Shunt><Pentose Shunt><Pentosephosphate Pathway><Pentosephosphate Shunt><Phb1 protein><Phb2 protein><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Physiopathology><Plasma Membrane><Primary Cell Cultures><Production><Prognosis><Programmed Cell Death><Proliferating><Protein Kinase B><Proteins><Proto-Oncogene Proteins c-akt><PtdIns 3-Kinase><Publishing><RAC-PK protein><RNA Expression><Recombinants><Reporting><Research><SARS-CoV-2 infection><SARS-CoV2 infection><Sampling><Scientist><Sepsis><Serum><Severe acute respiratory syndrome coronavirus 2 infection><Signal Transduction><Signal Transduction Systems><Signaling><Sphingolipid Microdomains><Sphingolipid-Cholesterol Rafts><Strains Cell Lines><Stress><Structure><Subcellular Process><Techniques><Testing><Therapeutic><Time><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Trauma><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Universities><Utah><Work><adulthood><bio-engineered><bio-engineers><bio-markers><bioengineering><biologic><biologic marker><biological engineering><biological signal transduction><biomarker><blood infection><bloodstream infection><c-akt protein><cardiac dysfunction><cardiac failure><cardiac metabolism><cardiac muscle><cardiac preservation><cardiomyocyte><cardioprotectant><cardioprotection><cardioprotective><clinical relevance><clinically relevant><cohort><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease-19><coronavirus infectious disease-19><cultured cell line><customs><cytokine><death risk><druggable target><enzyme linked immunoassay><experiment><experimental research><experimental study><experiments><gene modification><genetically modified><glucose metabolism><heart dysfunction><heart metabolism><heart muscle><heart preservation><hepatic body system><hepatic organ system><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inflammation marker><inflammatory marker><injuries><insight><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lipid raft><loss of function><mitochondrial><mitochondrial dysfunction><mortality><mortality rate><mortality ratio><mortality risk><mouse model><multiorgan failure><multiple organ system failure><murine model><myocardium disease><myocardium disorder><novel><overexpress><overexpression><oxidation><pathophysiology><pathway><plasmalemma><predictive biomarkers><predictive marker><predictive molecular biomarker><preservation><prohibitin><proto-oncogene protein RAC><proto-oncogene protein akt><rac protein kinase><related to A and C-protein><response><scaffold><scaffolding><sepsis patients><septic><septic patients><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><stem><transcription factor><transcriptomics><uptake>