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Principal Investigator: MARIA LEHTINEN
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $565,326
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Post-hemorrhagic hydrocephalus (PHH) is a leading cause of morbidity in premature infants. PHH is triggered
by germinal matrix intraventricular hemorrhage (IVH) that results in accumulation of cerebrospinal fluid (CSF) in
the brain compression of surrounding brain tissue, and permanent neurological deficits. While PHH is clearly
caused by an altered balance of CSF production and removal, the mechanisms are poorly understood, limiting
our ability to guide rational therapies. Here, we propose to examine two processes that could be manipulated
therapeutically to alleviate PHH: (1) ion and fluid transport by the choroid plexus (ChP), and (2) ventricular blood
clearance by macrophages. In adults under normal physiological conditions, sheets of specialized ChP epithelial
cells secrete CSF via an incompletely understood set of membrane proteins including NKCC1, a phosphorylation
activated bi-directional Na-K-Cl cotransporter. Strikingly, we recently discovered that NKCC1 participates in CSF
removal rather than CSF secretion during early stages of brain development. CSF-K+ levels are significantly
higher in embryos than adults, likely explaining this opposite direction of NKCC1 water transport8. Experimental
introduction of blood into the ventricles during development appears to further elevate CSF-K levels, and to drive
intracellular calcium activity in ChP epithelial cells, expression of the immediate early gene c-fos, and increased
expression/phosphorylation of NKCC1. Our findings suggest a novel counter-regulatory response to IVH in
premature infants: ChP absorption of CSF via NKCC1, driven by K+. We will test this hypothesis by determining
if NKCC1 activation either worsens or mitigates hydrocephalus in our mouse IVH model (Aim 1; preliminary data
suggests the latter). We also found that following IVH, blood products linger in the developing ventricles and may
account for the persistence of PHH. The brain's ventricles and the apical surface of the ChP are home to specific
macrophages known as Kolmer cells. While Kolmer cells have been implicated as responders to brain
hemorrhage, their scavenging and other functions have remained elusive. Our data suggest that during early
stages of brain development, ventricular macrophages/Kolmer cells are activated and recruited to the site of
blood leakage within the ventricle (Aim 2A) and that these macrophages are necessary and sufficient to clear
blood and/or inflammatory signals from the ventricles (Aim 2B, C). Collectively, our data suggest that the ultimate
severity of PHH depends on a developmental stage-specific interplay between blood products, ion
concentrations (e.g. [K]), immune and inflammatory reactions, and NKCC1 expression levels. An estimated 20%
of infants that experience intraventricular bleeds develop PHH. We suspect this is due to insufficient endogenous
compensatory responses. The ultimate goal of this proposal is to improve outcomes by laying the groundwork
for development of clinical treatments that boost endogenous removal of CSF and blood that drive the pathogenic
processes that lead to PHH. This proposal should also guide therapies for adult IVH and other conditions with
disrupted extracellular ionic homeostasis.
Terms: <2-photon><21+ years old><Abscission><Adult><Adult Human><Apical><Autoregulation><Biology><Bleeding><Blood><Blood Reticuloendothelial System><Brain><Brain Nervous System><Brain Pathology><Brain Trauma><Brain Ventricle><Brain hemorrhage><CSF clearance><Calcium><Causality><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell secretion><Cells><Cellular Secretion><Cerebral Palsy><Cerebral Ventricles><Cerebrospinal Fluid><Childhood><Choroid Plexus><Choroid Plexus Epithelium><Clinical><Clinical Treatment><DNA Therapy><Data><Demyelinations><Development><Developmental Delay><Developmental Delay Disorders><Diagnostic Method><Diagnostic Procedure><Diagnostic Technique><Drainage><Drainage procedure><Embryo><Embryonic><Encephalon><Epithelial Cells><Equilibrium><Etiology><Event><Excision><Extirpation><Extravasation><FOS gene><Fluids and Secretions><G0S7><Gene Transfer Clinical><Genetic><Genetic Intervention><Gestation><Goals><Hemorrhage><Home><Homeostasis><Hydrocephalus><Hydrocephaly><Hydrogen Oxide><Image><Immediate-Early Genes><Immune><Immunes><Infant><Inflammatory><Infusion><Infusion procedures><Intracellular Communication and Signaling><Intraventricular><Ions><K-Cl cotransporter><KCl cotransporter><Leakage><Liquid substance><MR Imaging><MR Tomography><MRI><MRIs><Macrophage><Magnetic Resonance Imaging><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mice><Mice Mammals><Modeling><Molecular><Morbidity><Morbidity - disease rate><Motion><Murine><Mus><Myelin><Mφ><NMR Imaging><NMR Tomography><Neonatal><Neurologic Deficit><Nuclear Magnetic Resonance Imaging><Operative Procedures><Operative Surgical Procedures><Optics><Outcome><Pathogenicity><Perinatal><Peripartum><Phagocytosis><Phosphorylation><Physiologic><Physiological><Physiological Homeostasis><Pregnancy><Premature Infant><Process><Production><Protein Phosphorylation><Proteins><Protooncogene FOS><Reaction><Removal><Reoperation><Repeat Surgery><Research><Resolution><Role><Route><Serial Magnetic Resonance Imaging><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Site><Specific Child Development Disorders><Spillage><Structure of choroid plexus><Supplementation><Surface><Surface Proteins><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><System><Testing><Therapeutic><Transgenic Mice><Traumatic Brain Injury><Ventricular><Viral><Water><Water Movements><Zeugmatography><absorption><adulthood><balance><balance function><biological signal transduction><bleeding in brain><blood loss><blood product><brain tissue><c fos><c-fos Gene><c-fos Proto-Oncogenes><causation><cerebral spinal fluid><cerebrospinal fluid clearance><chloride-cotransporter potassium><clinical development><clinical diagnostics><conditional knock-out><conditional knockout><demyelinate><develop therapy><developmental><disease causation><experience><experiment><experimental research><experimental study><experiments><extracellular><fluid><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genomic therapy><hemorrhagic stroke><homes><hydrocephalic><imaging><improved outcome><infants born premature><infants born prematurely><infusions><insight><intervention development><intraventricular hemorrhage><life span><lifespan><liquid><long-term sequelae><medical diagnostic><mouse model><murine model><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><optical><overexpress><overexpression><pediatric><postnatal><premature baby><premature infant human><preterm baby><preterm infant><preterm infant human><recruit><resection><resolutions><response><serial MRI><social role><spinal fluid><surgery><therapy development><traumatic brain damage><treatment development><trial regimen><trial treatment><two-photon><v-FOS FBJ Murine Osteosarcoma Viral Oncogene Homolog>