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Project

Identification of therapies targeting lipid metabolism and myelination for Charcot-Marie-Tooth disease type 1A using patient-derived Schwann cells

In the inherited demyelinating peripheral neuropathy Charcot-Marie-Tooth disease type 1-A (CMT1A), peripheral myelin protein 22 (PMP22) is duplicated in Schwann cells leading to abnormal differentiation and progressive demyelination. Cholesterol is essential for myelination and PMP22 regulates its trafficking: CMT1A rodent models overexpressing PMP22 show downregulated cholesterol and lipid metabolism with reduced transcription of genes required for myelin lipid biosynthesis, thus leading to myelin sheath alteration. In this scenario, dietary phospholipids ameliorate the disease phenotype but only post-translationally, without a concomitant change in lipid biosynthesis transcription. Several therapies have shown to work in these models subsequently failed in clinical trials probably due to the transgene overexpression, which induces artificial pathological symptoms that are not seen in humans. Therefore, in the lab, it has been generated human iPSC-derived Schwann cell lines to better mimic and study the pathology in vitro. In this project, we aim to apply a high-throughput screen to CMT1A patient-derived Schwann cells to find compounds that stimulate cholesterol and lipid metabolism transcriptionally thus to have a long-lasting beneficial effect. Finally, we want to study the behaviour of human healthy/CMT1A iPSC-derived Schwann cells by implanting them in the PNS of a humanized Schwann cell-depleted CMT1A animal model. One of the major problems of animal injection of stem cell-derived Schwann cells is their difficult tracking. Therefore, the optically transparent Zebrafish embryos can be used for our scope, exploiting its capability to absorb small chemicals from water. In this way, those compounds mostly effective on the transcriptional level of lipid-metabolism can be further validated in vivo, to find potential disease-modifying drugs.

Date:18 Jan 2021 →  Today
Keywords:Neurobiology, Neurodegeneration, iPSC, Microfluidic, CMT1A, Myelination
Disciplines:Neurological and neuromuscular diseases, Stem cell biology, Cell therapy, Single-cell data analysis, Medical lipidomics
Project type:PhD project