Modelling human choroid plexus development and the regulation of cerebrospinal fluid in health and disease

Our brain is floating in the cerebrospinal fluid (CSF) – a source of signalling factors, hormones and nutrients. The CSF is secreted by a single layer of cells called the choroid plexus (ChP), which forms the blood-CSF-barrier. The dynamic regulation of CSF signals delivered to the neural stem cells is critical for brain development. CSF abnormalities can lead to diseases such as microcephaly, autism and schizophrenia. My plan is to use the new model I recently developed of ChP organoids to better understand the dynamic changes in early ChP and CSF and how they influence brain development. First, using single-cell RNA sequencing and proteomics, we will study the origin of cellular diversity in the ChP and the contribution of different cell subtypes to the CSF proteome. We will validate these findings with foetal ChP tissue. Next, using ChP-cortical organoid, we will explore how CSF signals influence cortical development. We will investigate the effect of temporal secretion of CSF components on the neuroepithelial cell proliferation and differentiation using synchronised trafficking assays. Finally, we will investigate the role of the barrier in transport of immune cells across the ChP epithelium, characterise the trafficking mechanisms in health and diseases such as multiple sclerosis (MS).