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Principal Investigator: David Antonetti
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $661,256
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Stroke is a significant cause of adult disability in the US. Early treatment with thrombolytics or mechanical
thrombectomy can significantly improve neurological outcomes in patients with acute ischemic stroke.
However, following these acute interventions long term recovery care is primarily limited to treatments
designed to prevent stroke recurrence, and to rehabilitation therapies. Factors that can influence long term
prognosis, include age, stroke severity, infarct location, and comorbidities. Many stroke survivors do not
recover full function for normal activities with ~45% of working age adults unable to return to work by 6 to 12
months following stroke. Thus, a major challenge for stroke treatment is the identification of therapeutic
strategies that can help restore function and limit long term disability. In studies conducted in previous cycles of
this grant we have focused on understanding the pathways affecting acute stroke injury. We demonstrated that
during ischemic stroke, tissue plasminogen activator (tPA) acts on the parenchymal side of the neurovascular
unit (NVU) to increase blood brain barrier (BBB) permeability and symptomatic intracerebral hemorrhage
(sICH). Studies established that tPA cleavage releases an inhibitory domain activating platelet derived growth
factor-C (PDGFC) signaling through the PDGF-receptor-α (PDGFRα) in perivascular astrocytes ultimately
leading to downstream signaling by vascular endothelial cell growth factor (VEGF) and PKCβ in vascular
endothelial cells (ECs) regulating the tight junction complex through occludin phosphorylation. Our long-term
goal is to understand the molecular pathways activated during ischemic stroke and to identify interventions
that make stroke treatment safer and more effective. In this application we will build on these data and
examine the role of the tPA/PDGFRα/VEGF/PKCβ pathway in post-stroke neuroinflammation, and on the
downstream recovery pathways. Our central hypothesis is that in ischemic stroke tPA-mediated early events
in the NVU control both neuroinflammation and post-stroke recovery of brain function. We will test this
hypothesis in three specific aims that will identify the molecular mechanisms of this pathway during early post-
stroke neuroinflammation and on the resolution of neuroinflammation during the transition to healing and the
restoration of cerebral blood flow to the damaged brain tissue. Together, these studies will elucidate
mechanisms by with tPA controls both inflammation and collateral vessel growth and identify potential
interventions to promote long term functional recovery.
Terms: <21+ years old><Acquired brain injury><Acute><Adult><Adult Human><Affect><Age><Alteplase><Apoplexy><Assay><Astrocytes><Astrocytus><Astroglia><BBB permeabilization><BBB permeable><Binding><Bioassay><Biological Assay><Blood - brain barrier anatomy><Blood Vessels><Blood Volume><Blood flow><Blood-Brain Barrier><Body Tissues><Brain><Brain Injuries><Brain Ischemia><Brain Nervous System><Brain Vascular><Brain Vascular Accident><CD140a Antigens><CNS Nervous System><Caring><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell division><Cell membrane><Cells><Cellular Proliferation><Central Nervous System><Centrosome><Cerebral Brain Hemorrhage><Cerebral Hemorrhage><Cerebral Parenchymal Hemorrhage><Cerebral Stroke><Cerebral hemisphere hemorrhage><Cerebrovascular Apoplexy><Cerebrovascular Circulation><Cerebrovascular Stroke><Cerebrum Hemorrhage><Complex><Cytoplasmic Membrane><DNA Synthesis Factor><Data><Dynein><Dynein ATPase><Dynein Adenosine Triphosphatase><Dynein Adenosinetriphosphatase><Early Intervention><Early treatment><Encephalon><Endothelial Cell Growth Factor><Endothelial Cells><Endothelium><Event><FGF><Fibroblast Growth Factor><Fibroblast Growth Factor Gene Family><Fibroblast Growth Regulatory Factor><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Funding><Gene Deletion><Gene Expression><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Goals><Grant><Growth><Hemato-Encephalic Barrier><Imatinib><Infarction><Inflammation><Injury><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intracerebral Hemorrhage><Intravenous><Ischemic Encephalopathy><Ischemic Stroke><Leucocytic infiltrate><Light><Link><Location><Long term disability><Long-Term Care><MGC41878><Measures><Mechanics><Mediating><Medical Rehabilitation><Mice><Mice Mammals><Middle Cerebral Artery Occlusion><Minus End of the Microtubule><Mitotic><Molecular><Molecular Interaction><Motor><Movement><Murine><Mus><Mutation><Neuraxis><Neurologic outcome><Neurological outcome><Neutrophil Infiltration><Neutrophil Recruitment><Neutrophilic Infiltrate><Nongrowing End of the Microtubule><Occluding Junctions><PDGF Receptors><PDGF alpha Receptor><PDGF receptor α><PDGF-C><PDGF-CC><PDGF-R-alpha><PDGFR-α><PDGFRα><PKC-beta><PKC-β><PKCB><PKCβ><PRKCB><PRKCB1><PRKCB1 gene><PRKCB2><Pathway interactions><Patients><Permeability><Phase><Phase 2 Clinical Trials><Phase 3 Clinical Trials><Phase II Clinical Trials><Phase III Clinical Trials><Phosphorylation><Phosphorylation Site><Photoradiation><Plasma Membrane><Platelet Activation><Platelet-Derived Growth Factor Receptor><Platelet-Derived Growth Factor Receptor Alpha Polypeptide><Platelet-Derived Growth Factor alpha Receptor><Play><Prognosis><Proliferating><Protein Phosphorylation><Proteins><Publishing><Recombinant Tissue Plasminogen Activator><Recovery><Recovery of Function><Recurrence><Recurrent><Regulation><Rehabilitation><Rehabilitation therapy><Reporting><Research><Resolution><Role><Severities><Side><Signal Induction><Signal Transduction><Signal Transduction Systems><Signaling><Site><Staining method><Stains><Stroke><Stroke prevention><T-Plasminogen Activator><Testing><Therapeutic><Thrombectomy><Tight Junctions><Time><Tissue Activator D-44><Tissue Growth><Tissue Plasminogen Activator><Tissue-Type Plasminogen Activator><Tissues><VEGF><VEGFs><Vascular Endothelial Cell><Vascular Endothelial Growth Factors><Vascular Endothelium><Work><Zonula Occludens><acute cerebrovascular accident><acute stroke><adulthood><after stroke><ages><angiogenesis><antagonism><antagonist><astrocytic glia><biological signal transduction><blood flow in brain><blood-brain barrier permeabilization><blood-brain barrier permeable><bloodbrain barrier><bloodbrain barrier permeabilization><bloodbrain barrier permeable><body movement><brain attack><brain blood circulation><brain blood flow><brain damage><brain tissue><brain-injured><cell culture><cell cultures><cerebral blood flow><cerebral circulation><cerebral vascular><cerebral vascular accident><cerebro-vascular><cerebrocirculation><cerebrovascular><cerebrovascular accident><cerebrovascular blood flow><co-morbid><co-morbidity><comorbidity><comparable efficacy><comparative efficacy><compare efficacy><disability><early therapy><extended care><flow cytophotometry><functional recovery><functional restoration><gene deletion mutation><genome mutation><glial activation><glial cell activation><healing><improved><improved outcome><infarct><injuries><intervention design><interventional strategy><long term recovery><longterm care><mechanic><mechanical><mutant><neural inflammation><neuro-vascular unit><neuroinflammation><neuroinflammatory><neurovascular unit><novel><occludin><ontogeny><pathway><phase II protocol><phase III protocol><plasmalemma><platelet-derived growth factor C><platelet-derived growth factor receptor α><post stroke><poststroke><prevent><prevent stroke><preventing><protein kinase C beta><protein kinase C-β><protein kinase Cβ><rehab therapy><rehabilitative><rehabilitative therapy><resolutions><restoration><restore function><restore functionality><restore lost function><social role><stroke recovery><stroke survivor><stroke therapy><stroke treatment><stroked><strokes><systematic review><t-PA><therapy design><trafficking><transcriptomics><treating stroke><treatment design><vascular>