PROJECTS
The role of genetic code on MS disease trajectories
INVESTIGATORS – Inge R. Holtman, Bart Eggen, Erik Boddeke, Inge Huitinga
PROJECT – Multiple sclerosis disease development is highly heterogenous. For example, two MS patients with very similar symptoms at the beginning might show very divergent progression over time, while two other MS patients with very different symptoms at time of diagnosis, might show remarkable similarity in their disease progression. We currently don’t understand this heterogeneity very well, which makes it difficult to reliably predict the disease course. There are about two hundred positions in the genome identified that influence susceptibility to MS. However, it is largely unknown how these positions influence the likelihood to develop MS and how it progresses. In order to address this issue, we recently established the Netherlands Neurogenomics Database, in collaboration with the Netherlands Brain Bank (NBB, www.brainbank.nl). In this database, we will integrate clinical parameters, with neuropathological information, and genetic background from a wide range of donors with different brain diseases such as MS. We will use this database to study the effect of molecular and genetic mechanisms that are associated with MS and hope to obtain a better understanding of the heterogeneity of MS disease trajectories. The donors to the NBB are the true heroes of this (and many other) projects, because they enable us to set this up!
The hereditary predisposition in MS explained: In search of the important genes for MS in the cell types that matter.
INVESTIGATORS – Iris Jonkers, Karim Kreft, Jan Meilof
PROJECT – MS is caused due to a large part by our genetic material (DNA). Several regions in our DNA are associated with the onset of MS. How these regions participate and which are truly necessary is still poorly understood. That is why we will look at the building blocks in the regions to investigate which problems aberrant building blocks can cause in cells and organs important in MS: The immune system and the cells in the brain and spinal cord. We will do this with a new method called SuRE-SNP. SuRE-SNP can determine in many cell types, including immune and neuronal cells, which building blocks matter. This will reveal mechanisms that are affected in MS by these building blocks, and therefore we can determine more directly and precisely what the consequences are in MS disease processes and onset. Moreover, we will look at all genes associated with MS disease processes in genetic material of a large group of people that we have already collected and will test their functions in important cells. In this way we will be able to address the consequences of the genetic building blocks with great precision for MS, and hopefully detect new ways of treating MS.
Supported by the Dutch MS Research Foundation
Are somatic mutations associated with MS lesions and do they drive MS pathophysiology?
INVESTIGATORS – Susanne Kooistra, Inge Holtman, Rocio Vicario, Frederic Geissmann, Bart Eggen
PROJECT – Every cell in the human body contains DNA, the carrier of our genetic information, of which the sequence is largely identical in each cell. However, during (embryonic) development, a time of extensive cell division, changes appear in the DNA as a consequence of mistakes during replication. These changes, that occur during development, or later in life are called somatic mutations. Since these mutations only appear in some of the cells, humans are genetic mosaics. Depending on the particular change in the DNA and the exact location of the cells carrying the mutation, such mutations can contribute to disease. A clear example of this is the mutations that give rise to the initiation and growth of tumors. But also the neurodegeneration that occurs in histiocytosis patients is caused by such mutations. In case of histiocytosis, mutations occur in a particular cell type in the central nervous system, in
The aim of this project is to determine if, and to what extent such somatic mutations are present in the cells of the central nervous system of MS-donors and if these mutations contribute to disease etiology.
Supported by the Dutch MS Research Foundation