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Principal Investigator: Frank J Raucci
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
Fiscal Year: 2024
Award: $148,214
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Cardiovascular disease is the primary cause of death for patients with Duchenne muscular dystrophy (DMD).
Arrhythmia and cardiac fibrosis leading to dilated cardiomyopathy are the primary mechanisms of cardiac
mortality. Pannexins (Pxs), which are large conductance ion and small molecule channels, have been
implicated in other fibroproliferative diseases and are thought to be arrhythmogenic in other model of cardiac
disease. Loss of dystrophin, the primary defect in DMD, leads to elevated intracellular calcium (Ca2+) which is
also a primary effector of Pxs. The goal of this project is to investigate the mechanisms by which Px1
modulates the development of cardiac fibrosis and arrhythmogenesis in models of DMD cardiomyopathy.
Our preliminary data demonstrate a novel role for Px1 in the development of cardiac fibrosis and inducible
arrhythmia seen in the D2-mdx model of DMD. Genetic ablation of Px1 in the D2-mdx model (mdxPx1-/-)
rescues the cardiac phenotype, including normalization of cardiac fibrosis.as assessed by histopathology and
significant reduction in isoproterenol-induced ventricular ectopy. Based on these data, we hypothesize that
pathologically elevated intracellular Ca2+, a hallmark of this disease, leads to Px1 activation and results in
signaling cascades that activate apoptotic, oxidative, and inflammatory pathways that ultimately lead to
fibroblast activation and the development of cardiac fibrosis. We also hypothesize that Px1 channels represent
an independent mechanism for ventricular arrhythmia via generation of delayed after-depolarizations (DADs).
We with test these hypotheses using the 3 specific aims outlined in this proposal. In Aim 1, we will use
transgenic mice with global Px1 deletion in addition to pharmacological Px inhibition to determine if Px1
activation results in triggered arrhythmia. In Aim 2, we will identify the mechanism by which Px1 contributes to
cardiac fibrosis in DMD cardiomyopathy using pharmacological and genetic strategies. As Pxs are expressed
in both cardiomyocytes and cardiac fibroblasts, Aim 3 will test if fibroblast migration is dependent on Px1
activation in cardiomyocytes and/or fibroblasts using co-culture techniques for human induced pluripotent stem
cell cardiomyocytes (hiPSC-CMs) and cardiac fibroblasts. The completion of these studies will help to improve
our understanding of the mechanisms of cardiovascular disease in DMD and will provide the basis for further
investigation of a novel therapeutic target that has the potential to delay or prevent cardiac mortality in DMD
patients. Additionally, this proposal will allow a promising young physician scientist to gain important skill in
basic and translational studies in cardiac electrophysiology, cell signaling, and inflammation/fibrosis biology
under the expert guidance of a highly accomplished and dedicated mentorship committee. These new skills will
provide the foundation for a successful transition from junior investigator to an independently-funded academic
physician scientist.
Terms: <18 year old><18 years of age><ATP Dependent Proton Translocase><ATP phosphohydrolase (Ca(2+)-transporting)><ATP phosphohydrolase (H+-transporting)><Abbreviations><Ablation><Adenosine Triphosphatase Complex><Age><Apoptosis><Apoptosis Pathway><Apoptotic><Arrhythmia><Biology><Ca Release Channel-Ryanodine Receptor><Ca(2+)-Transporting ATPase><Ca2+ ATPase><Ca2+ transporting ATPase><Calcium><Calcium ATPase><Calcium Adenosine Triphosphatase><Calcium Pump><Calcium-Ryanodine Receptor Complex><Cardiac><Cardiac Arrhythmia><Cardiac Diseases><Cardiac Disorders><Cardiac Electrophysiologic Techniques><Cardiac Electrophysiological Diagnostics><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiovascular Diseases><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Locomotion><Cell Membrane Permeability><Cell Migration><Cell Movement><Cell Nucleus><Cell Signaling><Cells><Cellular Migration><Cellular Motility><Cessation of life><Childhood><Co-culture><Cocultivation><Coculture><Coculture Techniques><Complex><Congestive Cardiomyopathy><Cytoplasm><DMD cardiomyopathy><Data><Death><Dedications><Defect><Development><Diagnosis><Dilated Cardiomyopathy><Disease><Disorder><Duchene><Duchenne><Duchenne cardiomyopathy><Duchenne muscular dystrophy><Duchenne muscular dystrophy cardiomyopathy><Duchenne-Griesinger syndrome><Dysfunction><Dystrophin><Ellis-van Creveld (EvC) syndrome><F(0)F(1)-ATP Synthase><F(1)F(0)-ATPase><F0F1 ATPase><F1F0 ATPase Complex><Fibroblasts><Fibrosis><Fibrosis in the heart><Fibrosis in the myocardium><Fibrosis within the heart><Fibrosis within the myocardium><Fibrotic myocardium><Foundations><Functional disorder><Funding><Gene Expression><Generations><Genes><Genetic><Goals><H(+)-ATPase><H(+)-Transporting ATP Synthase><H(+)-Transporting ATPase><H(+)ATPase Complex><H+-Translocating ATPase><Heart Arrhythmias><Heart Diseases><Heart Muscle Cells><Heart failure><Heart myocyte><Histopathology><Home><Hypoxia><Hypoxic><Inflammasome><Inflammation><Inflammatory><Intracellular Communication and Signaling><Investigation><Investigators><Ions><Isoprenaline><Isopropyl Noradrenaline><Isopropylarterenol><Isopropylnoradrenaline><Isopropylnorepinephrine><Isoproterenol><Isuprel><Knock-out><Knockout><Link><MEFV gene product><Measures><Mediator><Mentorship><Modality><Modeling><Molecular><Morbidity><Morbidity - disease rate><Muscle Cells><Muscle Weakness><Muscular Dystrophies><Muscular Weakness><Myocardial depression><Myocardial dysfunction><Myocytes><Myodystrophica><Myodystrophy><Nucleus><Oxygen Deficiency><Pathologic><Pathway interactions><Patients><Persons><Phenotype><Physicians><Physiopathology><Play><Population><Primary Cardiomyopathy><Primary Myocardial Diseases><Process><Programmed Cell Death><Proteins><Proton-Translocating ATPase Complexes><Proton-Translocating ATPases><Pseudohypertrophic Muscular Dystrophy><Purine Receptors><Purinergic Receptors><Purinoceptor><Regulation><Research><Research Personnel><Researchers><Risk><Role><Ryanodine Receptor><Ryanodine Receptor Calcium Release Channel><Sarcoplasmic Reticulum><Scientist><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal Muscle><Stimulus><Stretching><Structure><Supportive Therapy><Supportive care><Symptoms><Testing><Time><Training Programs><Transgenic Mice><Transgenic Organisms><Ventricular><Ventricular Arrhythmia><Voluntary Muscle><X-linked dilated cardiomyopathy><X-linked muscular dystrophy><X-linked recessive muscular dystrophy><age 18 years><ages><benign X-linked recessive muscular dystrophy><biological signal transduction><boys><calcium transporting ATPase><cardiac dysfunction><cardiac electrophysiology><cardiac failure><cardiac fibrosis><cardiac function><cardiac rhythm><cardiomyocyte><cardioprotectant><cardioprotection><cardioprotective><cardiovascular disorder><cardiovascular health><cell motility><cell type><childhood pseudohypertrophic muscular dystrophy><classic X-linked recessive muscular dystrophy><coronary fibrosis><curative intervention><curative therapeutic><curative therapy><curative treatments><developmental><eighteen year old><eighteen years of age><endoplasm><experiment><experimental research><experimental study><experiments><extracellular><fibrotic heart><function of the heart><genetic approach><genetic strategy><heart disorder><heart dysfunction><heart electrophysiology><heart fibrosis><heart function><heart rhythm><hiPSC><homes><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><hydrogen transporting ATP synthase><improved><in vivo><induced human pluripotent stem cells><inflammatory modulation><marenostrin><membrane permeability><migration><mild X-linked recessive muscular dystrophy><mitochondrial ATPase><mortality><mouse model><murine model><muscle dystrophy><myocardial fibrosis><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathophysiology><pathway><pediatric><pharmacologic><preservation><prevent><preventing><programs><progressive muscular dystrophy of childhood><pseudohypertrophic adult muscular dystrophy><pseudohypertrophic muscular paralysis><pyrin><recruit><skills><small molecule><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transgenic><translational study><ventilation>