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Principal Investigator: Ke Cheng
Organization: COLUMBIA UNIV NEW YORK MORNINGSIDE
Fiscal Year: 2023
Award: $675,040
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Heart disease is the leading cause of death in the United States. About 875,000 Americans die from heart
disease each year, of which 50-60% deaths are caused by coronary artery disease (CAD). CAD, the most
common type of heart disease, can lead to heart attack and sudden death. While the survival patients can
progress into chronic cardiomyopathy and heart failure (HF) that is featured with myocardial fibrosis.
Myocardial fibrosis is associated with adverse outcomes. Currently, there is no specific drugs for cardiac
fibrosis. Stem cell or exosome therapy has been a promising option for fibrotic disease. However, the
challenges in quality control and GMP-grade large-scale production as well as the elusive mechanisms have
hindered the translational application. One solution to address the challenges is to identify specific molecules
that underlie the antifibrotic mechanisms of exosomes, and design nanoparticle carriers to deliver them. In our
preliminary studies that form the basis of proposal, we found that transcription factor Tcf21 is crucial in
suppressing myofibroblast activation, and exosome cargo long noncoding RNA (lncRNA)-TARID played as the
upstream enhancer of Tcf21 gene expression. Recently, the application of lipid nanoparticles (LNPs) has
expanded in a large scope of clinical trials for nucleic acid delivery. In this proposal, we aim to develop lncRNA
LNP for treatment of cardiac fibrosis. The overarching hypothesis is that LNPs loaded with lncRNA-TARID
(LNP-TARID) can upregulate Tcf21 to suppress myocardial fibrosis and improve cardiac functions. Our original
grant focuses on microRNA cargos in the exosomes, such as miR-21 and miR-146. From the sequencing
experiments, we serendipitously encountered other non-coding RNAs in the exosomes that play an essential
role in cardiac repair. LncRNA TARID is one of them. Our preliminary studies confirmed the therapeutic role of
LncRNA TARID in cardiac fibrosis. Our renewal submission will be focusing on this RNA agent, using LNP as
the delivery carrier. Aim 1: Optimization of LNP-TARID formulations and in vitro characterization; toxicity
studies in naïve animals. Aim 2: Determine the safety and efficacy of LNP-TARID treatment in mouse models
of acute and chronic MI. Aim 3: Translate the LNP-TARID therapy into a clinically-relevant pig model of
cardiac I/R injury. Our proposal is both mechanism-driven and product-oriented. The results from our research
will pave the ground for the development of new non-coding RNA therapies to treat myocardial infarction and
help us gain mechanistic insights on the Tcf21-regulated cardiac fibrosis pathways.
Terms: <Acute><Address><American><Animal Model><Animal Models and Related Studies><Animals><Applications Grants><Basal Transcription Factor><Basal transcription factor genes><Bioavailability><Biocompatible Materials><Biodistribution><Biological><Biological Availability><Biomaterials><Blood Platelets><Blood Vessels><Blood flow><Cardiac Diseases><Cardiac Disorders><Cardiac infarction><Cardiomyopathies><Cardiovascular Models><Cause of Death><Cell Body><Cells><Chronic><Cicatrix><Clinical Trials><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Development><Dimensions><Disease><Disorder><Drugs><Family suidae><Formulation><Functional RNA><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Goals><Grant><Grant Proposals><Heart><Heart Diseases><Heart Injuries><Heart failure><Human><In Vitro><Interdisciplinary Research><Interdisciplinary Study><Ischemia-Reperfusion Injury><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><Lytotoxicity><Marrow platelet><Mechanics><Medication><Micro RNA><MicroRNAs><Modern Man><Multidisciplinary Collaboration><Multidisciplinary Research><Myocardial><Myocardial Diseases><Myocardial Disorder><Myocardial Infarct><Myocardial Infarction><Myocardial Ischemia><Myocardial Ischemic Reperfusion Injury><Myocardial Reperfusion Injury><Myocardiopathies><Myofibroblast><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Paper><Pathway interactions><Patients><Pericardial cavity><Pharmaceutic Preparations><Pharmaceutical Preparations><Physiologic Availability><Pigs><Platelets><Play><Precision therapeutics><Progenitor Cells><Progress Reports><Publications><Quality Control><RNA><RNA Gene Products><RNA based therapeutics><RNA based therapy><RNA therapy><Reperfusion Damage><Reperfusion Injury><Research><Ribonucleic Acid><Rodent Model><Role><Safety><Scars><Scientific Publication><Selection Criteria><Stem Cell Development><Sudden Death><Suidae><Surface><Swine><Technology><Testing><Therapeutic><Therapeutic Effect><Thrombocytes><Toxic effect><Toxicities><Transcription Factor Proto-Oncogene><Transcription factor genes><Translating><United States><Untranslated RNA><Upstream Enhancer><Ventricular><adverse consequence><adverse outcome><atherosclerotic coronary disease><biologic><biological material><cardiac failure><cardiac fibrosis><cardiac function><cardiac infarct><cardiac injury><cardiac ischemia><cardiac repair><cardiac tissue engineering><clinical relevance><clinically relevant><coronary arterial disease><coronary attack><coronary fibrosis><coronary infarct><coronary infarction><coronary ischemia><cytotoxicity><design><designing><developmental><drug/agent><engineered heart tissue><exosome><experiment><experimental research><experimental study><experiments><first in man><first-in-human><full scale manufacturing><function of the heart><heart attack><heart disorder><heart function><heart infarct><heart infarction><heart ischemia><heart repair><improved><insight><large scale manufacturing><large scale production><lipid based nanoparticle><lipid nanoparticle><mass production><mechanic><mechanical><miRNA><miRNAs><model of animal><mouse model><murine model><myocardial fibrosis><myocardial ischemia/hypoxia><myocardium disease><myocardium disorder><myocardium ischemia><nano particle><nano-sized particle><nanoparticle><nanosized particle><new technology><noncoding><novel technologies><nucleic acid delivery><particle><pathway><pig model><piglet model><porcine><porcine model><pre-clinical study><precision therapies><precision treatment><preclinical study><progenitor cell delivery><progenitor cell development><safety study><social role><stem cell delivery><stem cell technology><stem cells><success><suid><swine model><therapeutic RNA><transcription factor><translational applications><vascular>