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Principal Investigator: Robin Harris
Organization: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
Fiscal Year: 2024
Award: $312,717
Funding agency: National Institute of General Medical Sciences
Project Summary
Cell death has a critical role in human development and recovery following injury or disease. This is
because dying cells produce signals that can significantly impact the behavior of the surrounding cells. The
identity and consequences of these signals are diverse and context dependent, but many are known to
regulate the survival, activity and proliferation of neighboring cells following injury. Thus, a better understanding
of how dying cells impact surviving tissue could uncover novel therapeutic interventions to improve healing and
regeneration following injury or disease.
While this signaling phenomenon has been characterized in apoptotic cell death, it is unclear whether
unregulated forms of cell death, such as necrosis, have a similar impact on tissue behavior and repair.
Necrosis is the rapid, disordered death of cells, which can occur in any tissue and is central to many human
conditions, including traumatic injuries (burns, frostbite), infections, and ischemic injuries like strokes and heart
attacks. Several factors released from necrotic cells have been identified, however, the identity of other signals
and whether they influence recovery has yet to be examined. The aim of this proposal is to investigate how
necrotic wounds impact surrounding tissues to influence recovery and regeneration.
Evidence that signals from dying cells impact nearby tissues first originated from studies of the larval
wing primordia in Drosophila, called imaginal discs. These tissues have significant regenerative capacity, the
study of which has led to important insights into the genetic events necessary for damage-induced tissue
recovery. However, most of these studies examine apoptosis-induced regeneration, limiting our understanding
of how cell death impacts surviving tissue to this type of injuries. To overcome this limitation, we have
established a genetic tool that allows us to trigger either necrosis or apoptosis in the developing wing disc, and
to genetically manipulate the surrounding cells that respond to each type of damage.
With this tool we found that discs successfully regenerate in each case, but via different mechanisms.
Notably, necrosis leads to widespread apoptotic cell death at a distance from the wound. This necrosis-
induced apoptosis, or NiA, is necessary to drive regenerative proliferation and is therefore critical for proper
recovery. The cause of NiA and how it promotes regeneration are currently unknown. Here, we propose to
characterize the genetic response that leads to successful regeneration following necrosis focusing on the role
of NiA. Our work aims to identifying how necrosis leads to NiA, understand how NiA promotes regeneration,
and comprehensively characterize the necrosis-induced regeneration program that results in NiA using whole
genome sequencing approaches. Together, the results of these experiments will contribute to our fundamental
understanding of tissue repair in response to necrosis, which is ultimately essential for developing novel
therapeutic approaches to treat necrotic wounds and promote regeneration in humans.
Terms: <21+ years old><AIF protein><Ablation><Adult><Adult Human><Apoptosis><Apoptosis Pathway><Apoptotic><Autoregulation><Behavior><Body Tissues><Burn injury><Burns><C-jun Amino-Terminal Kinase><C-jun Kinase-1><C-jun N-Terminal Kinase 1><Cardiac infarction><Cell Body><Cell Communication and Signaling><Cell Death><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cells><Cytoplasm><Dinoprostone><Disease><Disorder><Drosophila><Drosophila genus><Embryo Development><Embryogenesis><Embryonic Development><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Erinaceidae><Event><Frostbite><Generalized Growth><Generations><Genes><Genetic><Growth><Growth and Development><Growth and Development function><Health><Hedgehogs><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Homeostasis><Human><Human Development><Impairment><Induction of Apoptosis><Infection><Injury><Intracellular Communication and Signaling><JN Kinase><JNK><JNK Mitogen-Activated Protein Kinases><JNK1><JNK1 Kinase><JNK1 protein><JNK1A2><JNK21B1/2><Liver><Liver Cells><Liver Regeneration><Lytic><MAP Kinase 8><MAP Kinase 8 Gene><MAPK8><MAPK8 Mitogen-Activated Protein Kinase><MAPK8 gene><Membrane><Mice><Mice Mammals><Mitogen-Activated Protein Kinase 8><Modeling><Modern Man><Molecular><Murine><Mus><Myocardial Infarct><Myocardial Infarction><NGS Method><NGS system><Natural regeneration><Necrosis><Necrosis Induction><Necrotic><Organ><Outcome><PGE2><PGE2 alpha><PGE2alpha><PRKM8><Pathway interactions><Pattern><Physiological Homeostasis><Play><Process><Programmed Cell Death><Proliferating><Prostaglandin E2><Prostaglandin E2 alpha><Prostaglandin E2alpha><Recovery><Regeneration><Regenerative capacity><Role><SAP Kinase-1><SAPK/JNK><SAPK1 Mitogen-Activated Protein Kinase><SAPK1/JNK><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Stress-Activated Protein Kinase JNK1><Stress-Activated Protein Kinase gamma><System><Tissue Growth><Tissue Survival><Tissues><Traumatic injury><Wing><Work><adulthood><apoptosis inducing factor><biological signal transduction><burned><c-jun N-Terminal Kinase><cardiac infarct><cell sorting><cell type><coronary attack><coronary infarct><coronary infarction><disc regeneration><entire genome><epigenetically><experiment><experimental research><experimental study><experiments><fruit fly><full genome><gene manipulation><genetic approach><genetic manipulation><genetic strategy><genetically manipulate><genetically perturb><genome sequencing><healing><heart attack><heart infarct><heart infarction><hepatic body system><hepatic organ system><imaginal disc><improved><in vivo><injuries><injury recovery><insight><ischemia injury><ischemic injury><jun-NH2-Terminal Kinase><membrane structure><mitochondrial apoptosis-inducing factor><necrocytosis><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><next gen sequencing><next generation sequencing><nextgen sequencing><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ontogeny><pathway><programs><recovery after injury><recovery following injury><recovery post injury><regenerate><regenerate disc tissue><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><regeneration ability><regeneration capacity><regeneration following injury><regenerative><release factor><repair><repaired><response><social role><stress-activated protein kinase 1><stroke-like episode><stroke-like event><stroke-like injury><stroke-like insult><stroke-like ischemic event><tissue regeneration><tissue regrowth><tissue renewal><tissue repair><tissue specific regeneration><tissue wound><tool><transcriptomics><virtual><whole genome><wound><wounding><wounds>