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Principal Investigator: PRAVEEN BALLABH
Organization: ALBERT EINSTEIN COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $524,745
Funding agency: National Institute of Neurological Disorders and Stroke
Abstract
Intraventricular hemorrhage (IVH) remains a major neurological complication of prematurity that results in
cerebral palsy, hydrocephalus, and cognitive deficits. No effective therapy exists to prevent these disorders in
infants with IVH. IVH triggers inflammation in the periventricular germinal matrix and adjacent white matter,
resulting in maturational arrest of oligodendrocyte progenitor cells (OPCs) and myelination failure. Moreover,
there is increased CSF production and concurrent obstruction in CSF flow, which leads to hydrocephalus. IVH-
induced injury may disrupt the integrity and function of the blood brain barrier (BBB) and blood-CSF barrier
(BCB), allowing myeloid cells to infiltrate the brain, and fluids to exude from it, thus worsening the
consequences of IVH. Sphingosine 1 phosphate (S1P) is a lipid mediator and a key regulator of BBB and BCB
function. S1P binds and stimulates G-protein coupled receptors (S1PR1 through S1PR5). S1PR1 contributes
to vessel maturation, regulates adherens and tight junction assembly and function, and limits trafficking of
immune cells across the BBB. In contrast, S1PR2 promotes immune responses, increases BBB permeability,
and facilitates leukocyte entry into the brain. Thus, constitutively-expressed S1PR1 antagonizes S1PR2, which
is often induced under pathological conditions in the BBB. Both S1PR1 activation and S1PR2 inhibition offer
neuroprotection in brain injury models. However, the role of S1PR1 and S1PR2 in BBB and BCB damage,
hydrocephalus, and white matter injury is unclear in neonates with IVH. Our central hypotheses are: i) IVH
will induce inflammation, disrupt the BBB and BCB, and alter S1PR1 and S1PR2 expressions in the BBB and
BCB in both humans and rabbits and ii) modulation of S1PR1 and S1PR2 signaling by receptor subtype-
specific agents will restore BBB and BCB integrity, minimize cerebral inflammation, and reverse white matter
injury and hydrocephalus in preterm rabbits with IVH. We will test these hypotheses in a rabbit model of
glycerol-induced IVH and autopsy samples from human premature infants. In Aim 1, we will determine the
effect of IVH on a) BBB and BCB permeability and immune cell infiltration across the BBB and BCB, b)
endothelial tight and adherens junction, endothelial transcytosis, and key transporters, and c) transcriptional
changes in the capillary endothelium of the periventricular brain region and choroid plexus. The observations
made in rabbit will be validated in autopsy samples from preterm infants with and without IVH. In Aim 2 and 3,
we will evaluate the effect of S1PR1 and S1PR2 modulation on a) BBB and BCB permeability, endothelial tight
and adherens junction assembly, endothelial transcytosis and transcriptome, b) immune cell infiltration,
ventriculomegaly, and c) myelination and neurobehavior. We will also determine whether S1PR1 and S1PR2
signaling affect adherens and tight junction as well as myelination via sonic hedgehog and Rho-ROCK
pathways, respectively. These studies will enhance our understanding of S1P biology in the maturing brain and
hasten development of new therapies to minimize white matter injury and hydrocephalus in survivors of IVH.
Terms: <1,2,3-Propanetriol><1,2,3-Trihydroxypropane><21+ years old><Acquired brain injury><Adherens Junction><Adhering Junction><Adhesive Junction><Adult><Adult Human><Affect><Agonist><Anchoring Junction><Apoplexy><Autopsy><BBB disruption><BBB function><BBB permeabilization><BBB permeable><Behavioral><Binding><Biology><Blood><Blood - brain barrier anatomy><Blood Reticuloendothelial System><Blood Tests><Blood capillaries><Blood leukocyte><Blood-Brain Barrier><Brain><Brain Hypoxia-Ischemia><Brain Infarction><Brain Injuries><Brain Nervous System><Brain Vascular Accident><Brain region><Capillary Endothelial Cell><Cardiac Toxicity><Cardiotoxic><Cardiotoxicity><Cell Body><Cell Communication and Signaling><Cell Maturation><Cell Signaling><Cells><Cerebral Palsy><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cerebrum><Chaperone><Choroid Plexus><Circulation><Cognitive deficits><Complication><Coupled><Development><Disease><Disorder><Disseminated Sclerosis><Domestic Rabbit><Drugs><Edg Receptors><Encephalon><Endothelium><Engineering><Evaluation><Event><Exudate><Failure><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><G-Proteins><GPCR><GTP-Binding Proteins><GTP-Regulatory Proteins><Gene Transcription><Genetic Transcription><Glycerin><Glycerol><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><Hedgehog (Hh) signal transduction pathway><Hemato-Encephalic Barrier><Hematologic Tests><Hematological Tests><Hematology Testing><Hortega cell><Human><Hydrocephalus><Hydrocephaly><Immune><Immune infiltrates><Immune response><Immunes><Immunity><Immunological response><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Infant><Infiltration><Inflammation><Inflammatory Response><Injury><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Leucocytic infiltrate><Leukocytes><Leukocytes Reticuloendothelial System><Lipid A><Lipids><Liquid substance><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Marrow leukocyte><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Mice><Mice Mammals><Microglia><Modeling><Modern Man><Molecular Chaperones><Molecular Interaction><Morphology><Multiple Sclerosis><Murine><Mus><Myeloid Cells><NMR Imaging><NMR Tomography><Nervous System Injuries><Nervous System Physiology><Nervous System Trauma><Nervous System damage><Neurologic><Neurologic function><Neurological><Neurological Damage><Neurological Injury><Neurological function><Neurological trauma><Nuclear Magnetic Resonance Imaging><Obstruction><Occluding Junctions><Oryctolagus cuniculus><Pathologic><Pathway interactions><Permeability><Pharmaceutical Preparations><Premature Infant><Production><Progenitor Cells><Public Health><RNA Expression><Rabbits><Rabbits Mammals><Receptor Protein><Receptor Signaling><Recovery><Research><Role><S1P Receptor><SCmRNAseq><SHH><SHH gene><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Single cell mRNA seq><Sonic Hedgehog><Sphingosine-1-Phosphate Receptor><Stroke><Structure of choroid plexus><Survivors><Testing><Tight Junctions><Time Study><Tracer><Transcription><Ventricular><White Blood Cells><White Cell><Zeugmatography><Zonula Occludens><adulthood><antagonism><antagonist><astrogliosis><biological signal transduction><blood-brain barrier disruption><blood-brain barrier function><blood-brain barrier permeabilization><blood-brain barrier permeable><bloodbrain barrier><bloodbrain barrier disruption><bloodbrain barrier function><bloodbrain barrier permeabilization><bloodbrain barrier permeable><brain attack><brain damage><brain infarct><brain parenchyma><brain-injured><capillary><cerebral><cerebral vascular accident><cerebrovascular accident><cognitive defects><contrast enhanced><developmental><drug/agent><effective therapy><effective treatment><fluid><gitter cell><global gene expression><global transcription profile><hedgehog signaling><hedgehog signaling pathway><hh signaling pathway><host response><hydrocephalic><hypoxia/ischemia><immune cell infiltrate><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><infants born premature><infants born prematurely><injuries><insular sclerosis><interventional strategy><intraventricular hemorrhage><lipid mediator><liquid><mesoglia><microglial cell><microgliocyte><migration><myelination><necropsy><neonate><nervous system function><neurobehavior><neurobehavioral><neuroprotection><neuroprotective><neurotrauma><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oligodendrocyte precursor><oligodendrocyte progenitor><oligodendrocyte stem cell><pathway><perivascular glial cell><postmortem><premature><premature baby><premature infant human><prematurity><preterm baby><preterm infant><preterm infant human><prevent><preventing><receptor><restoration><rho><shRNA><short hairpin RNA><single cell mRNA sequencing><small hairpin RNA><smoothened signaling pathway><social role><sphingosine 1-phosphate><stem cells><stroked><strokes><substantia alba><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><trafficking><transcriptome><transcytosis><white blood cell><white blood corpuscle><white matter><white matter injury>