Remyelination

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Remyelination

Towards remyelination-stimulating therapies in demyelinating disorders

Fundamental Part

Coordinators: dr hab. Aleksandra Rutkowska, Prof. Bartosz Karaszewski

Project is devided into following themes:

  • A pilot study of relapsing experimental autoimmune encephalomyelitis model of multiple sclerosis in TDAG8 knock-out mice

    • Student: M. Opielka;
    Scientific Advisors: Prof. B. Karaszewski, dr hab. A. Rutkowska

    Elucidating the Role of Proton-Activated G Protein-Coupled Receptors in Neuroinflammation and Oligodendrocyte Function: Implications for Remyelination in Multiple Sclerosis:

    To maintain pH homeostasis, cells are required to sense acidic changes in their environment and respond accordingly. A T cell death-associated gene 8 (TDAG8, GPR65) has been shown to sense extracellular protons and stimulate differing signalling pathways. The expression of TDAG8 in normal tissue is primarily restricted to immune cells and often upregulated in solid tumors. However, high-powered GWAS studies identified TDAG8 as a candidate risk gene for multiple sclerosis (MS) and inflammatory bowel disease (IBD). While the function of TDAG8 in IBD has been repeatedly investigated only one study examined the effects of TDAG8 deficiency in the experimental autoimmune encephalomyelitis (EAE) model of MS. This project will further examine the role of TDAG8 in the pathophysiology of MS by employing a relapsing EAE model of MS.

  • Uncovering the Role of Myelination in the Pathogenesis and Progression of Alzheimer’s disease

    • PI: dr hab. A. Rutkowska

    Researcher: Piotr Pobiarzyn

    The primary objective of this project is to investigate the interplay between oligodendrocyte pathology and neurodegenerative diseases to uncover novel targets and mechanisms for therapeutic interventions and disease-modifying strategies to treat AD. It is unknown whether decreased myelination precedes Aβ pathology or whether Aβ affects the ability of oligodendrocytes to produce or rebuild myelin leading to neurodegeneration. We hypothesize that defective myelination and dysfunction of OPCs and/or mature oligodendrocytes play a vital role in the pathogenesis and progression of AD. Our main goals are to (1) decipher whether Aβ influences the ability of oligodendrocytes to myelinate, (2) to determine if restoring myelination and OPC function protects against Aβ pathology-associated neurodegeneration. Restoration of OPC/oligodendrocyte function may be a new therapeutic strategy for AD and other neurodegenerative diseases.

    Transclinical Part

    *Coordinators:     Prof. Bartosz Karaszewski, Barbara Kołodziej

    The study will involve patients from the University Clinical Centre who have been diagnosed with multiple sclerosis.In-vivo myelin quantification enables us to divide patients into “good” and “bad” remyelinators. To achieve this goal, the methods need to be highly accurate and specific. In the literature a plenty of myelin-specific methods were described but none of them were applied in clinical routine. In our project we intend to quantify myelin employing the most promising myelin-specific MRI techniques, including myelin water imaging (MWI) and inhomogeneous magnetization transfer (ihMT). Myelin water has specific properties and localization. It is trapped between lipid layers of myelin and its time T2 is shorter than T2 time for intra and extracellular water. Postprocessing of registered signal allow as to determine the contribution of myelin water to the total MRI signal in specific voxel. IhMT technique is used to study the exchange of magnetization between free water molecules and water molecules bound to macromolecules (such as proteins and lipids) in tissues. Both examinations will be conducted using a 3T MRI scanner equipped with fast sequences, allowing for clinically reasonable measurement times. Data analysis will be performed using dedicated software. Additionally, obtained results will be coregistered with PET imaging performed to asses myelin content in a brain. Radiotracers dedicated to this measurements bind to the myelin basic protein (MBP) and they are used for Alzheimer’s disease diagnosis. The main goal of co-registration will be to create complementary images so that the entire procedure is more precise and reproducible than individual MRI and PET methods. This project is is carried out in close cooperation with Division of Radiology and Division of Nuclear Medicine in University Clinical Centre of Gdańsk.

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