Project R-15378

Downstream PDE4D Signaling: Illuminating the Path to Myelin Regeneration in Multiple Sclerosis (Research)

Multiple sclerosis (MS) is a chronic autoimmune neurological disorder characterized by demyelinated lesions in the central nervous system, impaired oligodendrocyte precursor cell (OPC) differentiation, and axonal damage. Current therapies primarily target inflammation but fail to halt disease progression or prompt repair, highlighting the need for myelin regenerative therapies. Our research shows that elevating the levels of cAMP through inhibition of its hydrolyzing enzyme PDE4D promotes OPC differentiation and remyelination. However, the precise downstream signaling pathway activated by PDE4D inhibition in oligodendrocytes remains elusive, constituting the aim of this study. I hypothesize that treatment with PDE4D inhibitor RICE01 promotes differentiation of human induced pluripotent stem cell (iPSC)-derived OPCs and subsequent myelination through PKA and EPACdependent pathways. To test this hypothesis, I will conduct phosphoproteome and kinome analyses using the STK PamChip Microarray, followed by differential gene expression analysis through RNA sequencing. The biological relevance of the identified genes in oligodendrocyte development and myelination will be assessed through CRISPR/dCas9 gene manipulation in iPSC-OPC cultures and organotypic brain slices. This project aims to uncover novel and unconventional proteins and genes driving myelin regeneration, offering new therapeutic targets to mitigate demyelination and neurodegeneration in progressive MS patients.

01 November 2024 - 31 October 2028