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Principal Investigator: DEBABRATA MUKHOPADHYAY
Organization: MAYO CLINIC JACKSONVILLE
Fiscal Year: 2024
Award: $667,504
Funding agency: National Heart Lung and Blood Institute
Project Summary
The long-term objective of this application is to understand the molecular pathways of myocardial infraction (MI)-
mediated cardiac fibrosis and eventually heart failure. In our last grant cycle, we elucidated thoroughly the role
of Neuropilin-1 (NRP1), a multi-ligand receptor/adaptor and mediator of different signaling pathways including
TGFβ, in MI-induced cardiac pathogenesis, in particular fibrosis, and inflammation. Our preliminary data suggest
that conditional knockdown of NRP1 in the adult mice, either in cardiomyocytes (CM) or in endothelial cells (EC)
resulted varied phenotypes following cardiac injury (MI). In addition, our preliminary data from the single-nucleus
RNA sequencing (snRNA seq) using the cardiac tissues in a cell-specific manner and revealed marked changes
in gene expression patterns of key genes previously known to be associated with inflammation, cardiac
hypertrophy, fibrosis. In addition, we revealed microRNA (miR30s) showed differentially expressed in ECNRP1-/-
vs. CMNRP1-/- cells that correlated with HF genes. Hence, the scientific premise of this proposal is to reveal the
mechanistic role of divergent NRP1 spatiotemporal signaling in MI pathogenesis, and eventually to develop new
therapeutic targets and strategies to overcome progressive cardiac dysfunctions and overall heart failure. In this
regard, we will examine the spatiotemporal influence of NRP1 pathways for cardiac fibrosis following MI injury
as well as define the tissue-specific role of microRNAs regulated by NRP1 pathways on MI-induced fibrosis.
Finally, we will develop new therapeutic approaches to overcome cardio fibrosis following MI injury combining
novel NRP1 inhibitor (NRP1i) using novel targeted liposomal formulations. The current application is a multi-
disciplinary approach to reveal the spatiotemporal role of NRP1 in cardiac fibrosis/remodeling and identify new
targets to develop novel therapies to overcome one of the most common myocardial pathologies, which is an
unmet clinical need.
Terms: <21+ years old><A5 Antigen><ACE Inhibitors><Adult><Adult Human><Angiotensin I-Converting Enzyme Inhibitors><Angiotensin-Converting Enzyme Antagonists><Angiotensin-Converting Enzyme Inhibitors><Arrhythmia><Asymmetric Septal Hypertrophy><Blood flow><Body Tissues><Bone-Derived Transforming Growth Factor><Brachydanio rerio><Candidate Disease Gene><Candidate Gene><Cardiac><Cardiac Arrhythmia><Cardiac Diseases><Cardiac Disorders><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiomyopathies><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cicatrix><Clinical><Collaborations><Combined Modality Therapy><Cytometry><Danio rerio><Data><Death Rate><Diffuse><Drug Kinetics><Dysfunction><Endothelial Cells><Expression Signature><FLK1><Fibrosis><Fibrosis in the heart><Fibrosis in the myocardium><Fibrosis within the heart><Fibrosis within the myocardium><Fibrotic myocardium><Formulation><Functional disorder><Future><Gene Expression Profile><Genes><Grant><Heart><Heart Arrhythmias><Heart Diseases><Heart Hypertrophy><Heart Injuries><Heart Muscle Cells><Heart failure><Heart myocyte><Hereditary ventricular hypertrophy><Hypertrophic Cardiomyopathy><Hypertrophic Obstructive Cardiomyopathy><Hypoxia><Hypoxic><Idiopathic Hypertrophic Subvalvular Stenosis><Idiopathic hypertrophic subaortic stenosis><In Vitro><Inflammation><Injury><Intracellular Communication and Signaling><KDR gene><Kininase II Antagonists><Kininase II Inhibitors><Ligands><Mediating><Mediator><Mice><Mice Mammals><Micro RNA><MicroRNAs><Milk Growth Factor><Modeling><Molecular><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Myocardial><Myocardial Diseases><Myocardial Disorder><Myocardial depression><Myocardial dysfunction><Myocardiopathies><NRP1 Protein><Neuropilin-1><Npn-1 Protein><Nuclear RNA><Outcome><Oxygen Deficiency><Pathogenesis><Pathology><Pathway interactions><Pattern><Pharmacodynamics><Pharmacokinetics><Phenotype><Physiopathology><Platelet Transforming Growth Factor><RNA analysis><Receptor Protein><Recovery><Recovery of Function><Regulation><Regulator Genes><Role><Scars><Sema III Receptor><Semaphorin III Receptor><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Single-Nucleus Sequencing><Stimulus><Systolic heart failure><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Therapeutic><Tissues><Toxic effect><Toxicities><Trademark><Transcriptional Regulatory Elements><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><VEGF Receptors><VEGFR><VEGFR-2><VEGFR2><VPF Receptor><Validation><Vascular Endothelial Cell Growth Factor 165 Receptor><Vascular Endothelial Cell Growth Factor Receptor><Vascular Endothelial Growth Factor Receptor 2><Vascular Permeability Factor Receptor><Zebra Danio><Zebra Fish><Zebrafish><adulthood><biological signal transduction><cardiac dysfunction><cardiac failure><cardiac fibrosis><cardiac function><cardiac hypertrophy><cardiac injury><cardiomyocyte><clinical practice><combination therapy><combined modality treatment><combined treatment><compare to control><comparison control><coronary fibrosis><differential expression><differentially expressed><digital><fibrotic heart><function of the heart><functional recovery><gene expression pattern><gene expression signature><heart disorder><heart dysfunction><heart fibrosis><heart function><hypertrophic myocardiopathy><immune microenvironment><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><improved><inhibitor><injured><injuries><interdisciplinary approach><interstitial><knock-down><knockdown><lipid based nanoparticle><lipid nanoparticle><liposomal formulation><liposomal preparation><miRNA><miRNAs><mortality rate><mortality ratio><multi-modal therapy><multi-modal treatment><multidisciplinary approach><myocardial fibrosis><myocardium disease><myocardium disorder><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><pathophysiology><pathway><receptor><regulatory gene><response><sNuc-Seq><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><small molecular inhibitor><small molecule inhibitor><snRNA sequencing><snRNA-seq><social role><spatiotemporal><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><trans acting element><transcriptional differences><transcriptional profile><transcriptional signature><tumor immune microenvironment><tumor-immune system interactions><validations>