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Principal Investigator: JOANNE C CONOVER
Organization: UNIVERSITY OF CONNECTICUT STORRS
Fiscal Year: 2024
Award: $341,623
Funding agency: National Institute of Neurological Disorders and Stroke
Abstract
Infections, both bacterial and viral, have been linked to pediatric hydrocephalus and can impact the nascent
brain’s developmental programs. In fetal development, stem cells line the ventricles and provide neurons and
glia required for brain development; ventricle-contacting stem cells also generate a protective epithelial
monolayer of ependymal cells. As ependymal cells form a barrier wall along the ventricles, the remaining stem
cells are relegated to the subependymal zone and retain only a thin apical process in contact with the cerebral
spinal fluid. This unique arrangement characterizes the stem cell niche along the lateral walls of the lateral
ventricle and supports continued neurogenesis in postnatal development. It is known that certain viruses
preferentially target the ependymal cell lining of the ventricles resulting in loss of the structural support and barrier
functions provided by the ependymal cells. Infection during periods of ependymogenesis and neurogenesis
would critically impact the development and function of the stem cell niche.
The premise of this proposal is to model infection in a controlled manner and characterize damage to, and
reparative mechanisms of, the ventricular-subventricular zone stem cell niche over the course of post-infectious
hydrocephalus. Previous work mapped the lateral ventricles in 3D (mouse and human) to determine volume,
surface area and curvature changes over the course of development. New data from lineage tracing (multi-color
vectors) and live cell imaging will document stem cell-mediated ependymogenesis versus neurogenesis and
address stem cell depletion in normal development (Aim 1). The hypothesis that enlarged ventricles
(hydrocephalus) impact stem cell niche functions and compromise neurogenesis will first be tested using a
neurovirulent component of influenza, neuraminidase, which is known to cause hydrocephalus in mice (Aim 2).
After intraventricular injection of neuraminidase in embryonic and postnatal mice, sequelae of post-infectious
hydrocephalus, critical developmental time points and potential for stem cell-mediated repair will be examined.
Following examination of a univariant, neuraminidase, hydrocephalus model, bona fide post-infectious
hydrocephalus using a mouse variant of influenza will be modeled (Aim 3). Intraventricular, intraplacental and
intranasal routes will be assessed and the impact on the ventricular-subventricular stem cell niche and its
functions will be examined. The hypothesis that induction and severity of influenza-induced post-infectious
hydrocephalus can be mitigated by prior homologous or heterologous immunity will also be tested. These studies
will define the impact that post-infectious hydrocephalus has on a critical stem cell niche and its capacity for
regenerative repair – guiding treatment strategies for post-infectious hydrocephalus.
Terms: <21+ years old><3-D><3-Dimensional><3D><Acylneuraminyl hydrolase><Address><Adhesives><Adult><Adult Human><Anterior><Apical><Area><Brain><Brain Nervous System><Cell Body><Cell Count><Cell Cycle><Cell Differentiation><Cell Differentiation process><Cell Division Cycle><Cell Line><Cell Number><Cell surface><CellLine><Cells><Cerebrospinal Fluid><Childhood><Cleaved cell><Color><Coupled><Data><Developing fetus><Development><Disease><Disorder><Electroporation><Embryo><Embryonic><Embryonic Ventricle><Encephalon><Enzyme Gene><Enzymes><Ependyma><Ependymal Cell><Ependymal Tissue><Ependymocyte><Epithelium><Experimental Designs><Fetal Development><Fore-Brain><Forebrain><Glia><Glial Cells><Grippe><Human><Hydrocephalus><Hydrocephaly><Immune Cell Activation><Immunity><Infection><Influenza><Influenza A><Influenza A virus><Influenza Virus><Influenza Viruses Type A><Influenzavirus A><Injury><Intranasal Administration><Intranasal Drug Administration><Intraventricular><Intraventricular Injections><Kolliker's reticulum><Label><Lateral><Leanness><Life><Link><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Maps><Measures><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Mice><Mice Mammals><Modeling><Modern Man><Monitor><Murine><Mus><N-Acylneuraminate Glycohydrolases><NMR Imaging><NMR Tomography><Neonatal><Nerve Cells><Nerve Unit><Neural Cell><Neuraminidase><Neurocyte><Neuroglia><Neuroglial Cells><Neurons><Non-neuronal cell><Nonneuronal cell><Nuclear Magnetic Resonance Imaging><Oligosaccharide Sialidase><Orthomyxovirus Type A><Pathogenesis><Pathologic><Position><Positioning Attribute><Process><Production><Progenitor Cells><Property><Prosencephalon><Radial><Radius><Recovery><Regenerative capacity><Resistance><Resolution><Route><Sampling><Severities><Sialidase><Sialoglycoproteins><Slice><Strains Cell Lines><Subependymal><Surface><Testing><Thinness><Time><Type A Influenza><Variant><Variation><Ventricular><Viral><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Work><Zeugmatography><adult youth><adulthood><astrogliosis><cellular differentiation><cerebral spinal fluid><class development><course development><course material development><cultured cell line><developmental><electroporative delivery><exo alpha sialidase><flu serotype><flu strain><flu subtype><flu viral strain><flu virus strain><gene electrotransfer><hydrocephalic><immune activation><improved><in utero><influenza serotype><influenza strain><influenza subtype><influenza viral strain><influenza virus strain><influenzavirus><injuries><lateral ventricle><live cell image><live cell imaging><live cellular image><live cellular imaging><monolayer><mouse model><murine model><nerve cement><neurogenesis><neuronal><neurovirulence><pediatric><post-natal development><post-natal period><postnatal><postnatal development><postnatal period><prenatal><progenitor cell division><progenitor cell fate><progenitor cell function><progenitor cell niche><progenitor cell proliferation><progenitor cell renewal><progenitor division><progenitor fate><progenitor function><progenitor niche><progenitor proliferation><progenitor renewal><programs><public health relevance><reconstruction><regeneration ability><regeneration capacity><regenerative repair><repair><repaired><reparative ability><reparative capacity><reparative potential><resistant><resolutions><response><spatiotemporal><spinal fluid><stem and progenitor cell division><stem and progenitor cell fate><stem and progenitor cell function><stem and progenitor cell niche><stem and progenitor cell proliferation><stem and progenitor cell renewal><stem and progenitor function><stem cell depletion><stem cell division><stem cell exhaustion><stem cell fate><stem cell fatigue><stem cell function><stem cell niche><stem cell proliferation><stem cell renewal><stem cells><subventricular zone><three dimensional><treatment strategy><unborn><vector><ventricular system><virus protein><young adult><young adulthood>