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Principal Investigator: Fernando Francisco Gonzalez
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $460,447
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY/ABSTRACT
Neonatal stroke is an important cause of death and disability, and diagnosis is often delayed. There is
insufficient knowledge regarding repair mechanisms that occur in response to focal ischemia-reperfusion injury
that is the most common cause of early stroke. Angiogenesis, fibrosis, and perivascular cell repopulation occur
in close proximity, with paracrine signaling supporting endothelial cell interactions that are vital for repair.
Modulating this neurovascular niche may be a potential target for enhancing outcomes after ischemic injury in
the developing brain. Erythropoietin and cell-based therapies have emerged as promising delayed treatment
strategies for stroke, although the mechanism of their benefit is still not entirely clear. It is likely that dynamic
release of pro-angiogenic growth factors and activation of signaling pathways downstream of erythropoietin
receptor have differential effects on endothelial cell subtypes in distinct brain regions and at different time
points after injury. In addition, the defined role of local fibrosis in injury progression and repair following early
focal brain injury is unknown. Effectively inducing long-term, functional angiogenesis requires understanding
and mimicking mechanisms that occur in the developing brain. Our objectives are to understand local
angiogenesis and fibrosis in ischemic and peri-infarct regions following focal ischemia-reperfusion
injury in the developing brain, and to determine the mechanisms of regeneration and repair with
delayed erythropoietin by focusing on the vascular response. In Aim 1, we will test the hypothesis that
endothelial tip cells at the vascular front are critical for angiogenesis following neonatal stroke, and that
delayed erythropoietin will enhance angiogenesis and alter endothelial cell-subtype gene expression profiles to
promote tip cell programs. In Aim 2, we will quantify fibroblasts and perivascular cells in the ischemic core and
peri-infarct penumbra in the acute, subacute, and chronic stages after stroke and determine how erythropoietin
signaling impacts local fibrosis and repair. Finally, in Aim 3, we will determine and modify specific signaling
pathways to test the hypothesis that dynamic endothelial cell signaling modulated by erythropoietin is crucial
for promoting local angiogenesis following focal brain injury. This will determine critical, modifiable pathways
important for injury progression and repair following neonatal stroke. Our primary hypothesis is that delayed
erythropoietin treatment will promote vascular growth and remodeling, reduce subacute fibrosis and
astrocytic proliferation in the ischemic core, and enhance perivascular signaling to improve
histological and functional outcomes after neonatal stroke. Together, these three aims will explore the
roles of specific cellular subtypes and pathways in recovery after focal brain injury, with the broader goal of
optimizing therapeutic strategies to improve long-term outcomes after a common cause of full-term brain injury
that currently has no therapy.
Terms: <0-4 weeks old><Acquired brain injury><Acute><Adventitial Cell><Angiogenesis Inhibition><Angiogenic Inhibition><Apoplexy><Area><Astrocytes><Astrocytus><Astroglia><Behavioral><Blood Vessels><Brain><Brain Injuries><Brain Nervous System><Brain Vascular Accident><Brain region><Cause of Death><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell Therapy><Cell-to-Cell Interaction><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chronic><Cicatrix><Critical Paths><Critical Pathways><Data><Diagnosis><Dose><Dysfunction><ECSF><EPO-R><Early treatment><Encephalon><Endothelial Cells><Endothelium><Epoetin><Erythropoietin><Erythropoietin Receptor><Expression Signature><Ferroprotoporphyrin><Fibroblasts><Fibrosis><Focal Brain Injuries><Functional disorder><Functional impairment><Gene Expression Profile><Gene Transcription><Generalized Growth><Genetic Transcription><Goals><Growth><Growth Agents><Growth Factor><Growth Substances><Heme><Histologic><Histologically><Hypoxia><Hypoxic><Immunologic Subtyping><Immunophenotyping><Infarction><Injury><Intracellular Communication and Signaling><Ischemia><Ischemia-Reperfusion Injury><KO mice><Knock-out Mice><Knockout Mice><Knowledge><Measures><Mediating><Methodology><Mice><Mice Mammals><Middle Cerebral Artery Occlusion><Molecular><Murine><Mus><Natural regeneration><Neonatal><Neonatal Brain Injury><Newborn Infant><Newborns><Null Mouse><Outcome><Oxygen Deficiency><Paracrine Communication><Paracrine Signaling><Pathway interactions><Pericapillary Cell><Pericytes><Perinatal arterial ischemic stroke><Perivascular Cell><Phase><Physiopathology><Population><Pre-Clinical Model><Preclinical Models><Proliferating><Proteins Growth Factors><Protoheme><Publishing><RNA Expression><Recovery><Regeneration><Reperfusion Damage><Reperfusion Injury><Role><Rouget Cells><Scars><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stroke><Stromal Cells><Testing><Therapeutic><Time><Tissue Growth><Transcription><VEGF><VEGFs><Validation><Vascular Endothelial Growth Factors><Work><after stroke><angiogenesis><astrocytic glia><biological signal transduction><brain attack><brain damage><brain-injured><cell mediated therapies><cell type><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><cerebral vascular accident><cerebrovascular accident><conditional knock-out><conditional knockout><disability><early therapy><economic impact><erythrocyte colony stimulating factor><ferroheme><functional outcomes><gene expression pattern><gene expression signature><hematopoietin><immunophenotype><improved><improved outcome><infarct><injuries><ischemia injury><ischemic injury><mesenchymal stromal cell><neonatal brain><neonatal stroke><neuro-vascular><neurovascular><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><newborn child><newborn children><notch><notch protein><notch receptors><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ontogeny><pathophysiology><pathway><perinatal arterial stroke><perinatal ischemic stroke><post stroke><post-stroke angiogenesis><poststroke><poststroke angiogenesis><programs><public health relevance><regenerate><repair><repaired><response><social role><socio-economic><socio-economically><socioeconomically><socioeconomics><stroked><strokes><trafficking><transcriptional profile><transcriptional signature><treatment strategy><validations><vascular>