Multiple Sclerosis
MS is a central nervous system disease, characterized by demyelination, neurodegeneration and a varying degree of inflammation that may be primary or occur secondary to myelin damage. The long held belief that MS is an autoimmune disease in which the peripheral immune system attacks CNS-antigens is gradually being challenged and the possibility that processes indigenous to the CNS trigger disease is increasingly gaining attention. This research line is directed at elucidating the pathogenetic mechanisms underlying both white and gray matter lesions in MS.
Our main topics include
a) role of inflammation (inside the brain compartment and the meninges) and the potential role of Epstein-Barr virus in induction of the immune response.
b) differences in the pathology of gray versus white matter lesions including the hypothalamus, hippocampus, spinal cord and the pathological characterization of abnormalities seen on MRI scans.
c) the role of the mitochondrion as a cause of primary or secondary neurodegeneration.
d) the characterization of a potentially very early lesion in the disease process, the preactive lesion.
e) aspects of remyelination in MS and the cuprizone model
f) role of autoimmunity to neuronal antigens in MS
g) epigenetic mechanisms in microglial activation and monocyte/macrophage differentiation in MS and EAE
h) characterization of innate immune responses in MS
To examine the mechanisms underlying these aspects of pathology we have implemented animal models of MS and have established in vitro human CNS cultures
These models in conjunction with neuropathological studies of MS allow translation to the clinic.
Congenital White Matter Disease
There is a large number of congenital diseases, characterized by abnormal myelination, all rare. Prof. M. van der Knaap (VUmc) has a unique expertise in this field and has characterized at least 2 "new" disease entities. The pathological characterization of these has been the project of P. van der Voorn. The genes for these diseases have been characterized and as a follow-up of an NWO project (conditional) knock-out mice for these genes have been generated. The characterization of the pathology of these mice, spontaneous and after interventions is the subject of a project (M. Bugiani). This project is directed by Prof. van der Knaap, with M. Bugiani as an AGIKO positioned at the department of Pathology. The knock-out mice of the genes of 2 of these diseases took a long time to materialize, but very recently they came into being and M. Bugiani will now start characterizing them.
Although the primary cause of multiple sclerosis (MS) is unknown, the widely-accepted view is that aberrant (auto)immune responses possibly arising following infection(s) are responsible for the destructive inflammatory demyelization and neurodegeneration in the central nervous system (CNS). This notion and the limited access to human brain tissue early in the disease has led to the development of different in vitro human culture systems as well as animal models to research the disease. These models are used alongside human pathological studies to uncover novel pathways and molecules that can be exploited for therapeutic strategies and biomarkers for translational studies.
In brief the aims of these studies therefore are to:
" elucidate the (earliest) steps in lesion formation in MS
" validate in vitro models to modulate the disease process
" improve MRI diagnostics of MS
" understand regional differences within the CNS in MS
" clinical translation including identified drug targets and biomarkers
Paul van der Valk MD PhD - program leader
Sandra Amor - academic staff
Peter van den Elsen PhD - academic staff
Evert Jan Kooi - PhD student
Maarten Witte - PhD student
Chris Verlaan MSc - PhD student
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