Tuesday, May 14, 2024
5/14/2024
PROJECT SUMMARY Perinatal white matter injury (WMI) is a common sequela of neonatal brain injury. One of the leading causes of neonatal brain injury and morbidity in premature infants is post-hemorrhagic hydrocephalus (PHH). PHH is triggered by germinal matrix and/or intraventricular hemorrhage (IVH) that results in accumulation of cerebrospinal fluid (CSF) in the brain ventricles. This accumulation of CSF can cause compression of surrounding brain tissue and injury to the developing white matter. Specifically, in PHH the degree of ventricular dilation is correlated with severity of WMI as measured by decreased myelination and increased axonal injury, cellularity, and cytoplasmic vacuolation. Myelination in the central nervous system (CNS) has been previously identified as dependent upon Autotaxin (ATX), which can be sourced via the CSF. The choroid plexus (ChP) is the tissue which controls the amount and composition of the CSF and therefore helps instruct the developing nervous system. Here, we examine expression and availability of ChP-secreted ATX influencing white matter development and myelination of the mouse CNS and hypothesize this may be an important signaling axis which could be therapeutically harnessed to treat WMI associated with PHH. The Lehtinen Lab's single nucleus sequencing data demonstrates ATX expression across all epithelial cell clusters, thereby suggesting the epithelial cells may secrete ATX into the CSF. In preliminary studies we confirm that the ChP secretes ATX and show that ATX abundance in the ChP and CSF increase throughout development, with a particularly noticeable upregulation in the critical postnatal window associated with myelination of the CNS in mouse. In Aim 1, I will determine the effect of ChP-specific ATX modulation on myelination using advanced in vivo mouse manipulation techniques to selectively delete or overexpress ATX in the ChP. In Aim 2, I will further explore role for ATX in the pathophysiological mechanisms of WMI using the lab's translationally relevant mouse model of neonatal PHH following IVH. The results of these studies will inform our understanding of the mechanisms of hemorrhage induced WMI and will help guide rational intervention strategies for treatment, thereby improving quality of life for patients and caregivers. The proposed research will take place at Boston Children's Hospital under the guidance of Dr. Maria Lehtinen, an expert in the field of choroid plexus and CSF biology, and will provide training in ChP in vivo manipulation techniques, glial biology, exposure to clinical experience, and in the design of translationally relevant preclinical studies. We will routinely consult with collaborators and mentors who are experts on both white matter development and the neurologic sequelae associated with PHH of prematurity. The results from this proposal will result in first-authored publications and a large body of support for a K99/R00 application, with the goal of launching an independent academic career.
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