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Principal Investigator: KIMARA L TARGOFF
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $546,099
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Due to the limited ability to mount a regenerative response in injured myocardium, cardiac dysfunction remains
a key cause of morbidity and mortality. Coronary artery disease leads to myocardial infarction which results in
fibrotic scarring, adverse remodeling, and heart failure. In contrast to adult mice and humans, neonatal mice
and adult zebrafish retain the ability to undergo cardiomyocyte dedifferentiation and proliferation, ultimately
stimulating cardiac regeneration following injury. Deciphering the fundamental transcriptional networks shared
in development and regeneration will fuel our ability to awaken endogenous reparative mechanisms. In zebrafish,
embryonic cardiac transcriptional factors necessary for cardiogenesis, such as Nkx2.5, are galvanized following
injury to stimulate cardiomyocyte production. Our preliminary studies reveal that Fibulin 5, an extracellular matrix
(ECM) glycoprotein functioning downstream of Nkx2.5, is upregulated in the injured heart. Moreover, we show
that fibulin loss-of-function fish exhibit impaired regenerative capacity and crucial roles in migration and tissue
elasticity. In this proposal, we will test the hypothesis that activation of Nkx2.5 is necessary to produce an ECM
milieu comprise of cardinal pro-regenerative proteins such as Fibulin 5 that can be harnessed to augment cell-
based therapies for patients. In Aim 1, we will elucidate the myriad mechanisms by which Nkx2.5 directs effectors
to mediate deposition and remodeling of ECM elements employing mass spectrometry-based proteomic
strategies. In Aim 2, we postulate that Fibulin 5 modulates TGF-β signaling to promote epicardial invasion and
titrate tissue stiffness. We will dissect both the canonical and non-canonical TGF-β pathways to identify the key
signal transducers downstream of Fibulin 5. Using time lapse imaging of cardiac slices, we will probe the
intertwined movements of epicardial and myocardial cells in real time as they penetrate deep into the wound.
We will benefit from atomic force microscopy to measure elastic modulus in regenerating myocardium to uncover
the requirement of Fibulin 5 in preserving a malleable microenvironment to promote migration. In Aim 3, we will
investigate the premise that Fibulin 5 is a vital component of the regenerative ECM with potential to enhance
scar resolution by evaluating hiPSC-CMs mobility in vitro and host-graft integration in vivo. Together, we
anticipate that our proposed work will launch a novel paradigm highlighting the importance of embryonic ECM
components such as Fibulin 5 downstream of Nkx2-5 in promoting epicardial and cardiomyocyte migration and
tissue elasticity to enhance therapeutic strategies for patients.
Terms: <21+ years old><ARMD3><Address><Adult><Adult Human><Assay><Atomic Force Microscopy><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biological Assay><Body Tissues><Bone-Derived Transforming Growth Factor><Brachydanio rerio><Cancers><Cardiac><Cardiac Malformation><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac development><Cardiac infarction><Cardiocyte><Cardiomyopathies><Cell Body><Cell Communication and Signaling><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><Cell Therapy><Cell-Extracellular Matrix><Cells><Cellular Infiltration><Cellular Migration><Cellular Motility><Cicatrix><Common Rat Strains><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Cues><DANCE gene><DANCE protein><Danio rerio><Data><Dedications><Defect><Deposit><Deposition><Development><ECM><EVEC><Elastic Tissue><Elasticity><Elements><Embryo><Embryonic><Engraftment><Ensure><Epicardium><Exhibits><Extracellular Matrix><FBLN5><FBLN5 gene><Fibulin 5><Fishes><Force Microscopy><Fostering><Gene Activation><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Glycoproteins><Heart><Heart Injuries><Heart Malformation><Heart Muscle Cells><Heart failure><Heart myocyte><Homeo Domain><Human><Human Genetics><Human Migration / Distribution><Impairment><In Vitro><Infarction><Injury><Intracellular Communication and Signaling><Invaded><Investigation><Ischemia><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><Malignant Neoplasms><Malignant Tumor><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Mediating><Methods><Mice><Mice Mammals><Milk Growth Factor><Modeling><Modern Man><Modulus><Morbidity><Morbidity - disease rate><Morphogenesis><Movement><Murine><Mus><Mutate><Myocardial><Myocardial Diseases><Myocardial Disorder><Myocardial Infarct><Myocardial Infarction><Myocardial Ischemia><Myocardial depression><Myocardial dysfunction><Myocardiopathies><Myocardium><Natural regeneration><Outcome><Pathway interactions><Patients><Pattern><Penetration><Platelet Transforming Growth Factor><Play><Production><Prognosis><Proliferating><Proteins><Proteomics><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Rat><Rats Mammals><Rattus><Regeneration><Regenerative capacity><Regenerative response><Regulation><Research><Resolution><Role><Scanning Force Microscopy><Scars><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Stress><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Therapeutic><Time><Tissues><Titrations><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transducers><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><UP50><Up-Regulation><Upregulation><Work><Zebra Danio><Zebra Fish><Zebrafish><abnormal heart development><adulthood><atherosclerotic coronary disease><biological signal transduction><body movement><cardiac dysfunction><cardiac failure><cardiac imaging><cardiac infarct><cardiac injury><cardiac ischemia><cardiac muscle><cardiac preservation><cardiac regeneration><cardiac repair><cardiac scanning><cardiogenesis><cardiomyocyte><cell mediated therapies><cell motility><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><congenital cardiac abnormality><congenital cardiac anomalies><congenital cardiac disease><congenital cardiac disorder><congenital cardiac malformation><congenital heart abnormality><congenital heart anomaly><congenital heart disease><congenital heart disorder><congenital heart malformation><coronary arterial disease><coronary attack><coronary infarct><coronary infarction><coronary ischemia><developmental><experiment><experimental research><experimental study><experiments><extracellular><fibulin><gain of function><gene regulatory network><healing><heart attack><heart development><heart dysfunction><heart formation><heart imaging><heart infarct><heart infarction><heart ischemia><heart muscle><heart preservation><heart regeneration><heart repair><heart scanning><hiPSC><homeodomain><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><human migration><iPS cell derived cardiomyocytes><iPSC derived cardiomyocytes><improved><in vivo><induced human pluripotent stem cells><induced pluripotent stem cell derived cardiomyocytes><infarct><injured><injuries><injury response><injury to the myocardium><innovate><innovation><innovative><insight><loss of function><malignancy><migration><morphogenetic process><mortality><myocardial injury><myocardial ischemia/hypoxia><myocardial migration><myocardium disease><myocardium disorder><myocardium ischemia><neonatal mice><neoplasm/cancer><novel><pathway><preservation><regenerate><regeneration ability><regeneration based therapy><regeneration capacity><regeneration following injury><regeneration function><regeneration potential><regeneration response><regeneration therapy><regenerative><regenerative cell><regenerative function><regenerative functionality><regenerative potential><regenerative therapeutics><regenerative therapy><repair><repaired><resolutions><response><response to injury><social role><time use><tissue wound><transcription factor><transcriptome sequencing><transcriptomic sequencing><transplant therapy><transplant treatment><transplantation therapy><transplantation treatment><wound><wounding><wounds>