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Principal Investigator: Olujimi A Ajijola
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $527,667
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
Cardiac injury predisposes patients to heart failure (HF), and ventricular tachycardia/fibrillation (VT/VF).
Development of HF and VT/VF after cardiac injury is tightly linked to sympathetic neural remodeling. Although
several medications targeting cardiac sympathetic excess reduce mortality following cardiac injury, significant
shortcomings of these drugs include off-target effects, limited efficacy, and focus on downstream
consequences of neural remodeling such as excess catecholamine release, rather than preventing it upstream.
In this proposal, we build on strong preliminary data from humans, porcine, and murine models demonstrating
that satellite glial cell (SGC) activation is a central feature of chronic cardiac injury. Activated glia release
inflammatory cytokines, ATP, and other factors that modulate neuronal function. Chemogenetic upregulation of
glial calcium signaling (as observed in activated glia) increase cardiac sympathetic neuronal excitability,
synaptic efficacy, and tonic firing. Based on these novel findings, the goal of this proposal is to test the
hypothesis that satellite glial activation and enhanced glial-neuronal signaling is a primary driver of cardiac
sympathetic neuronal dysfunction, heart failure and VT/VF after cardiac injury.
We will test our hypotheses using novel tools from a multidisciplinary team of investigators in 3 specific
aims in two murine models of cardiac injury (ischemia-reperfusion and dilated cardiomyopathy). We will test
whether following cardiac injury, satellite glial cell activation within stellate ganglia exacerbates neuronal and
cardiac remodeling (structural and functional) to promote LV dysfunction and VT/VF (Aim 1). We will
investigate the mechanisms by which cardiac injury activates SGCs in stellate ganglia after injury (Aim 2).
Finally, we will determine whether targeting glial Gq-GPCR Ca2+ signaling or Cx43-mediated glia-neuron/glial-
glial communication mitigates adverse remodeling and arrhythmogenesis following cardiac injury (Aim 3). The
results of this proposal will 1) indicate whether and how satellite glial cell activation contributes to sympathetic
imbalance after cardiac injury; and 2) determine whether targeting satellite glial cell activation offers
therapeutic potential in chronic cardiac injury.
Terms: <Ablation><Animals><Arrhythmia><Astroprotein><Attenuated><Calcium Ion Signaling><Calcium Signaling><Cardiac><Cardiac Arrhythmia><Cardiac Diseases><Cardiac Disorders><Cardiac infarction><Cardiomyopathies><Catecholamines><Cause of Death><Cell Communication and Signaling><Cell Signaling><Cervicothoracic Ganglion><Chronic><Chronic Disease><Chronic Illness><Communicating Junction><Communication><Congestive Cardiomyopathy><Connexin 43><Connexin43><Cx43><Data><Development><Dilated Cardiomyopathy><Disease><Disorder><Drugs><Dysfunction><Electrophysiology><Electrophysiology (science)><Fibrosis><Functional disorder><Future><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GFA-Protein><GFAP><GPCR><Gap Junctions><Genetic><Glia><Glial Cells><Glial Fibrillary Acid Protein><Glial Fibrillary Acidic Protein><Glial Intermediate Filament Protein><Goals><Health><Heart><Heart Arrhythmias><Heart Diseases><Heart Injuries><Heart failure><Human><Hyperactivity><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Injury><Intracellular Communication and Signaling><Investigators><Ischemia><Kolliker's reticulum><LV remodeling><Left Ventricular Dysfunction><Left Ventricular Remodeling><Levarterenol><Levonorepinephrine><Link><Low-resistance Junction><Mediating><Medical><Medication><Mice><Mice Mammals><Modeling><Modern Man><Morphology><Murine><Mus><Myocardial Diseases><Myocardial Disorder><Myocardial Infarct><Myocardial Infarction><Myocardiopathies><Myocardium><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Nervous System><Neural Cell><Neurocyte><Neuroglia><Neuroglial Cells><Neurologic Body System><Neurologic Organ System><Neuronal Dysfunction><Neuronal Transmission><Neurons><Neurophysiology / Electrophysiology><Nexus Junction><Non-neuronal cell><Nonneuronal cell><Noradrenaline><Norepinephrine><Patients><Pharmaceutical Preparations><Physiopathology><Play><Prevention><Process><Purines><Reperfusion Therapy><Research Personnel><Researchers><Role><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Stellate Ganglias><Stellate Ganglion><Structure of stellate ganglion><Supporting Cell><Sympathetic Ganglia><Sympathins><Synapses><Synaptic><Techniques><Testing><Therapeutic><Transgenic Mice><Up-Regulation><Upregulation><Ventricular Arrhythmia><Ventricular Tachycardia><Viral><attenuate><attenuates><axon signaling><axon-glial signaling><axonal signaling><beta-adrenergic receptor><biological signal transduction><cardiac failure><cardiac infarct><cardiac injury><cardiac muscle><cell type><chronic disorder><chronic pain><coronary attack><coronary infarct><coronary infarction><cytokine><death risk><developmental><drug/agent><electrophysiological><glia signaling><glial activation><glial cell activation><glial signaling><heart attack><heart disorder><heart infarct><heart infarction><heart muscle><human data><human model><inflammatory disease of the intestine><inflammatory disorder of the intestine><inhibitor><injuries><injury to organs><intestinal autoinflammation><left ventricle abnormality><left ventricle remodeling><model of human><mortality><mortality risk><mouse model><multidisciplinary><murine model><myocardium disease><myocardium disorder><nerve cement><nerve signaling><neural><neural control><neural dysfunction><neural regulation><neural signaling><neurochemical><neurochemistry><neuromodulation><neuromodulatory><neuronal><neuronal excitability><neuronal signaling><neuroregulation><neurotransmission><novel><organ injury><pathophysiology><pig model><piglet model><porcine model><prevent><preventing><release factor><reperfusion><side effect><social role><swine model><synapse><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><tool><β-adrenergic receptor>