Title
Supporting the oligodendrocyte-neuron coupling: pulling back to curtain on downstream PDE4D signalling (Research)
Abstract
Multiple sclerosis (MS) is a chronic disorder characterized by inflammation-induced demyelinated lesions in the central nervous system (CNS). During the early stages of MS, the limited repair is mediated by oligodendrocyte precursor cell (OPC) differentiation and subsequent remyelination. Nevertheless, during the later stages of MS, the endogenous repair mechanisms fail, leaving axons chronically demyelinated, leading to prominent neurodegeneration. Even though the currently available therapies are becoming more reliable in the early stages of MS, no effective treatment strategy exists that halts disease progression or reverses CNS damage. Hence, there is an unmet medical need for novel therapies stimulating neuro- and myelin regeneration. My preliminary data show that inhibiting the enzymatic breakdown of cAMP via PDE4D inhibition stimulates OPC differentiation, (re)myelination, and neurite outgrowth, a process depending on the enzymatic isoform inhibited. Yet, the downstream mechanism of how intracellular cAMP alterations mediate these different processes remains unknown. Therefore, in this project, I aim to identify the underlying pathways activated upon increasing cAMP levels, by means of PDE4D inhibition, in both neurons and oligodendrocytes. By positioning the downstream signaling cascade and defining the nature of downstream cascade activation, I will identify and subsequently validate novel, more specific, targets to enhance neuro- and myelin regeneration in MS.
Period of project
01 October 2023 - 30 September 2026