PhD Projects

Zuurman, M.W. (Mike) : Regulation of the CC chemokine SLC in mice brain immunology

Zuurman, M.W. (Mike)
E-mail : M.W.Zuurman@med.rug.nl

Department of Medical Physiology
University of Groningen
Bloemsingel 10
9712 KZ Groningen

Telephone number:
+31 50 3632706

Supervisors:
Dr. K. Biber
Prof. Dr. H.W.G.M. Boddeke

Period of employment:
01-09-1999 - 01-09-2003

Financed by:
University of Groningen
Chemotactic cytokines (Chemokines) are small proteins (7-10kD), that function as chemical guides to migrating cells of the immune system. By following the trail of chemokines, these cells can be directed to areas of inflammation or tissue damage. Chemokines can be divided into four subfamilies on the basis of a conserved cysteine motif in their chemical structure: C chemokines, where there is only one cysteine unit at the conserved position, CC chemokines, where the cysteines residues are adjacent, CXC chemokines, where the two cysteines are separated by another amino acid residue and finally CX3C chemokines, where the cysteines are separated by three different amino acids.

The role of chemokines in brain immunology is currently a new area of research. A variety of chemokines are expressed in the central nervous system (CNS) and there is evidence showing increased expression in inflammatory neurodegenerative diseases as Multiple Sclerosis and Alzheimer's disease. In MS for instance, the oligodendritic myeline tracks surrounding neuronal extensions are degraded as a result of an autoimmune response of brain-resident immune cells (e.g. microglia) and periferal immune cells that migrate from the blood, through the blood brain barrier (BBB) into brain tissue. However, little is known about the function of chemokine expression in the brain. One could assume that, as in other tissues, chemokines function primarily to attract leukocytes to sites of inflamed brain tissue. Interestingly, as brain cells can express chemokine receptors themselves, it is tempting to suggest that chemokines participate in cell-cell communication between cells of the CNS. Most chemokines in the brain are expressed by glial cells (i.e. astrocytes and microglia). Our group has recently found evidence that the CC chemokine secondary lymhoid tissue chemokine (SLC) was specifically expressed by cortical neurons. Although the binding of chemokines to their receptors in general is highly redundant (e.g. multiple chemokines can bind to the same chemokine receptor and chemokines can bind to more than one receptor), SLC is one of the few chemokines that binds almost exclusively to the receptor CCR7, almost, as new evidence indicates that SLC may also bind to the CXC receptor CXCR3.

The aim of the present project is to answer a number of SLC related questions:
What is the effect of SLC on brain cells?
Which cells express SLC under which conditions?
Which type of receptor is bound by SLC on which type of brain cell?
Which intracellular biochemical pathways are induced upon binding of SLC?
How is transcription of SLC regulated?
What is the role of SLC in inflammatory neurodegeneration?
By means of a variety of laboratory techniques we will attempt to shed some light on this matter. Briefly, In vitro cultures of primary neonatal astrocytes, neurons and microglia will be subjected to different stimuli and by means of (single cell) reverse-transcription and polymerase-chain-reaction the intracellular chemokine encoding RNA content will be analyzed. In situ hybridization and immunohistochemistry will be performed on cultured primary cells and cell lines, besides in vivo slices of whole brain and specific brain areas. Furthermore, effects of SLC on cultured cells under different conditions will be analyzed by intracellular calcium measurements, patching, microinjection, proliferation and chemotaxis assays and ELISA readings.

The author studied Biology at the University of Groningen (neurobiology and medical physiology). Besides his interests in biology, the author is involved in "mostly harmless" occupations as: music (performing and composing), computer-related stuff, Star Trek, reading Science Fiction (Herbert, Vance, Asimov, Feist), his social life, and in-depth, head-to-head, loudmouth discussions with his friends about "life, the universe and everything". "So long and thanks for all the fish."
Last modified:October 10, 2012 10:24