Characterizing stress response variability in immature oligodendrocytes in the context of inflammation

Lead Research Organisation: University of Warwick
Department Name: School of Life Sciences

Abstract

Exposure to prenatal adversities leads to neurodevelopmental (NDDs) and neuropsychiatric (NPDs) disorders. NDDs and NPDs share common pathomechanisms, which prominently include the dysregulation of stress-responsive pathways. Alcohol exposure and systemic inflammation leading to neuroinflammation are among the most prevalent brain prenatal environmental insults. Prenatal alcohol exposure (PAE) leads to fetal alcohol spectrum disorders (FASD; 1% of births in Western countries), which shows overlap with attention deficit hyperactivity disorders (ADHD), anxiety, major depression, vulnerability to addiction, autism spectrum disorders (ASD) and schizophrenia (SZ). Neuroinflammation (e.g. due to intrauterine infection during pregnancy) is a leading cause of prematurity and the commonest cause of NDDs/NPDs (e.g ASD, ADHD, SZ), via diffuse white matter injury (DWMI). In previous lab work, by using epigenomic and transcriptomic analyses in a robust mouse model of neuroinflammation, the activation of complex stress response pathways underlying the blockade of the maturation of oligodendrocyte precursors (OPCs) has been unravelled. The overarching aim of this project is to identify extremely vulnerable OPC subpopulations and decipher the hierarchy and dynamics of combinatory stress-responsive transcription pathways that contribute to block the OPC maturation trajectory, as specific cellular and molecular targets for future therapeutic strategies. For this, single-cell epigenomic (scATAC-Seq) and single-cell transcriptomic (scRNA-seq) approaches will be used to identify the most attractive candidates in the stress-responsive transcription pathways. These candidates will be used in pharmacological pilot studies targeting the identified vulnerable OPC populations to ameliorate their myelination potential in the future.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M01116X/1 01/10/2015 30/09/2023
2265139 Studentship BB/M01116X/1 30/09/2019 29/09/2023 Zoi Ioannidou