Sunday, May 11, 2025
5/11/2025
Disease Mechanisms of Prenatal and Pediatric Acquired Hydrocephalus - 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.
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