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Principal Investigator: Isabella Reichardt
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2024
Award: $43,841
Funding agency: National Heart Lung and Blood Institute
Project Summary
Dilated cardiomyopathy (DCM) is a highly prevalent inherited cardiac disease, characterized by systolic
dysfunction, eccentric hypertrophy, and left ventricle dilation. While pharmacologic and mechanical treatments
have been shown to partially improve cardiac function, these results are often short lived and highly variable
from patient to patient. Moreover, recent studies have demonstrated that epigenetic and matrix dysregulation
can persist, even in patients with improved systolic function after treatment. Given that aberrant chromatin
remodeling and extracellular matrix (ECM) deposition have been identified as drivers of dilated remodeling—and
that chromatin and ECM remodeling can become irreversible over time—it is crucial to understand the time-
dependent effects of DCM mutations on reversing maladaptive remodeling at the genome, myocyte, and matrix
levels. The central hypothesis of this proposal is that the reversibility of the DCM phenotype is time-dependent
due to the accumulation of permanent ECM and chromatin remodeling as the disease progresses. To complete
this proposal, I will utilize a DCM mouse model created by the Davis lab which contains a mutation (I61Q) in
cardiac troponin C (cTnC) that directly decreases the myofilament’s Ca2+ sensitivity, leading to eccentric
hypertrophy, systolic dysfunction, and left ventricle dilation. Importantly, expression of this mutant can be
temporally controlled with doxycycline to specifically test our central hypothesis. In this proposal I will 1)
Determine the time-dependent effects of I61Q cTnC expression on myocyte, matrix, and chromatin accessibility,
2) Examine the reversibility of DCM remodeling in myocyte, matrix, and chromatin accessibility at different stages
of the disease, and 3) Determine if myocytes retain epigenetic memories of the mechanical disequilibrium caused
by DCM. Improving our understanding of the time-dependent reversibility of DCM remodeling will better inform
therapeutic targets and treatment windows for patients with DCM. Moreover, completion of this project will
enhance Bella’s training as an independent scientist and prepare her to one day become a professor in
cardiovascular engineering. Receiving the NIH F31 predoctoral fellowship will facilitate important experiments
and training that will aid in her pursuit of this career goal. In this project, Bella will gain expertise in multi-omic
approaches—such as proteomics, RNAseq, and ATACseq—which are growing in popularity due to their
unbiased screening capabilities. The UW Genomics Core will assist Bella in learning how to effectively use these
tools, which will not only benefit this project but will also be an incredibly useful skillset for Bella’s future career.
Given the clinical relevance of this project, we have engaged Farid Moussavi-Harami, MD, an acting physician-
scientist who practices cardiology within the UW Department of Medicine. Dr. Moussavi-Harami’s input as a
clinician will be crucial for ensuring our research questions and aims remain relevant to patients, and his
mentorship throughout this project will enhance Bella’s training and career development as she aims to
eventually run a lab with an emphasis in translational therapeutics and technologies for cardiovascular diseases.
Terms: <ATAC sequencing><ATAC-seq><ATACseq><Actin Filaments><Actin-Activated ATPase><After Care><After-Treatment><Aftercare><Age><Age Months><Assay for Transposase-Accessible Chromatin using sequencing><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiac Failure Congestive><Cardiology><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Causality><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell-Extracellular Matrix><Cells><Cellular Matrix><Chromatin><Collagen><Congestive Cardiomyopathy><Congestive Heart Failure><Coupled><Cyclicity><Cytoskeletal System><Cytoskeleton><DNA Methylation><Data><Deposit><Deposition><Dilated Cardiomyopathy><Disease><Disorder><Dose><Doxycycline><Dysfunction><ECM><EFRAC><Ejection Fraction><Engineering><Ensure><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Etiology><Extracellular Matrix><Family suidae><Fellowship><Fibroblasts><Fibrosis><Functional disorder><Future><Gene Expression><Gene Transcription><Generations><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genome><Genomics><Goals><Heart><Heart Decompensation><Heart Diseases><Heart Hypertrophy><Heart Vascular><Heart failure><Hereditary><Human><Hypertrophy><In Vitro><Induced DNA Alteration><Induced Mutation><Induced Sequence Alteration><Inherited><Injury><Intracellular Communication and Signaling><Learning><Left Ventricles><Left ventricular structure><Link><Mechanics><Medicine><Memory><Mentors><Mentorship><Mesenchymal Progenitor Cell><Mesenchymal Stem Cells><Mesenchymal progenitor><Mesenchymal stromal/stem cells><Mice><Mice Mammals><Microfilaments><Modeling><Modern Man><Murine><Mus><Muscle Cells><Mutate><Mutation><Myocardial depression><Myocardial dysfunction><Myocardium><Myocytes><Myofilaments><Myosin ATPase><Myosin Adenosine Triphosphatase><Myosin Adenosinetriphosphatase><Myosins><NIH><National Institutes of Health><Nature><Organ><Outcome><Patients><Periodicity><Pharmacological Treatment><Phenotype><Physicians><Physiopathology><Pigs><Point Mutation><Progressive Disease><Proteomics><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Repression><Research><Resolution><Rhythmicity><Running><Scientist><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Suidae><Swine><Symptoms><Technology><Testing><Therapeutic><Time><Training><Transcription><Transgenic Mice><Treatment Failure><Troponin C><United States National Institutes of Health><Vibramycin><ages><alpha-6-Deoxyoxytetracycline><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><biological signal transduction><calcium binding troponin C><cardiac dysfunction><cardiac failure><cardiac function><cardiac hypertrophy><cardiac muscle><cardiovascular disorder><career><career development><causation><chromatin remodeling><chronic heart failure><circulatory system><clinical relevance><clinically relevant><congenital dilated cardiomyopathy><disease causation><effective therapy><effective treatment><epigenetic memory><epigenetically><epigenome><experiment><experimental research><experimental study><experiments><familial dilated cardiomyopathy><function of the heart><genome mutation><healing><heart disorder><heart dysfunction><heart function><heart muscle><hereditary dilated cardiomyopathy><improved><inherited dilated cardiomyopathy><inhibitor><injuries><intracellular skeleton><mechanic><mechanical><mechanical stimulus><mesenchymal stromal progenitor cells><mesenchymal-derived stem cells><mouse model><multiomics><multiple omics><murine model><mutant><palliative><panomics><pathophysiology><patient variability><patient variation><pharmacologic><porcine><post treatment><pre-doc><pre-doctoral><predoctoral><pressure><professor><resolutions><response><screening><screenings><skills><suid><therapeutic target><therapy failure><tool><transcriptome sequencing><transcriptomic sequencing><transgene expression><translational therapeutics><translational therapy><variability between patients><variation between patients>