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Principal Investigator: Junsu Kang
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $382,090
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
Adult mammals poorly regenerate injured hearts. In contrast, adult zebrafish possess a remarkable capacity to
regenerate damaged hearts. Combined with available genetic tools, this capacity makes zebrafish a powerful
system for deciphering the mechanisms underlying heart regeneration. Upon injury, the endocardium and
epicardium are rapidly activated to secrete paracrine factors that facilitate heart regeneration. Heart regeneration
research has focused mostly on identifying the secreted factors that trigger regenerative programs, yet little is
known about the regulatory mechanisms controlling their expression, a proximal step in the regenerative process.
Proper spatiotemporal regulation of these genes is essential for the intricate and tightly coordinated processes
underlying cardiac regeneration. Thus, elucidating gene regulatory mechanisms governing injury-responsive
gene expression will provide insights into potential therapeutic strategies based on stimulating paracrine
effectors. Previously, we identified leptin b (lepb) as an injury-induced factor secreted by the endocardium.
Importantly, we showed that the cardiac regeneration enhancer linked to lepb (LEN) is robustly activated by
cardiac injury, maintains activity during regeneration, and then returns to a naïve state upon completion of
regeneration. We also identified a cardiac injury-responsive enhancer linked to interleukin 11a (il11a), which
encodes a proregenerative cytokine structurally similar to lepb. We showed that zebrafish injury-responsive
enhancers drive reporter-gene expression in injured mouse hearts, indicating that the mechanisms mediating
injury-induced enhancer function are evolutionarily conserved. Based on these findings, we propose two aims to
decipher gene regulatory mechanisms governing heart regeneration. The central hypothesis is that cardiac
injury-responsive enhancers establish the transcriptional state of genes encoding paracrine factors that facilitate
heart repair. Aim 1 will determine the transcriptional mechanisms underlying cardiac injury-responsive enhancer
activity. We discovered that cardiac LEN (cLEN) is not only activated by injury but also actively repressed in the
absence of injury. We will employ transgenic assays, genetic and pharmacological approaches, as well as
epigenomic and computational analyses to test the hypothesis that repression and activation mechanisms
collectively determine cardiac injury-responsive enhancer function to confer injury-dependent cardiac gene
transcription. Aim 2 will use loss-of-function and gain-of-function studies to define how il11a controls heart
regeneration and to dissect its injury-responsive enhancer. Elucidating the transcriptional mechanisms and
function of crucial enhancer-regulated factors secreted upon cardiac injury will transform knowledge on how
injury signals are transduced to facilitate heart regeneration.
Terms: <21+ years old><Active Oxygen><Adult><Adult Human><Assay><Automobile Driving><Bar Codes><Bioassay><Biological Assay><Brachydanio rerio><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Computer Analysis><Cues><Danio rerio><Data><Development><Elements><Endocardium><Enhancers><Epicardium><Fishes><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><Generations><Genes><Genetic><Genetic Transcription><Genome><Goals><Heart><Heart Injuries><Heart Muscle Cells><Heart failure><Heart myocyte><Injury><Interleukins><Intracellular Communication and Signaling><Knock-in><Knowledge><Leptin><Link><MAP Kinase Kinase 1><MAP2K1><MAP2K1 gene><MAPK/ERK Kinase 1><MAPKK1><MEK-1><MEK1><MKK1><Mammalia><Mammals><Mediating><Mice><Mice Mammals><Mitogen-Activated Protein Kinase Kinase-1><Modeling><Morbidity><Morbidity - disease rate><Murine><Mus><Natural regeneration><Ob Gene Product><Ob Protein><Obese Gene Product><Obese Protein><Oxygen Radicals><PRKMK1><Pathway interactions><Pro-Oxidants><Process><Proliferating><RNA Expression><Reactive Oxygen Species><Regeneration><Regenerative capacity><Regenerative research><Regenerative response><Regulatory Element><Reporter><Reporter Genes><Reporting><Repression><Role><Signal Transduction><Signal Transduction Systems><Signaling><System><Testing><Therapeutic><Transcription><Transgenic Organisms><Zebra Danio><Zebra Fish><Zebrafish><adulthood><barcode><biological signal transduction><cardiac damage><cardiac failure><cardiac injury><cardiac regeneration><cardiac repair><cardiomyocyte><computational analyses><computational analysis><computer analyses><cytokine><developmental><driving><epigenomics><eye regeneration><gain of function><genetic approach><genetic strategy><global gene expression><global transcription profile><heart damage><heart regeneration><heart repair><in vivo><injured><injuries><injury response><innovate><innovation><innovative><insight><knockin><loss of function><mortality><mutant><overexpress><overexpression><paracrine><pathway><pharmacologic><programs><regenerate><regeneration ability><regeneration capacity><regeneration research><regeneration response><regeneration studies><regenerative><regenerative studies><response to injury><social role><spatiotemporal><tool><transcriptome><transgenic>