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Molecular mechanisms of ifn-y-induced mhc class i i gene expression inmacrophages. Cooperation and interaction among transcriptional regulators


Research objectives and content
The tight regulation of MHC class II gene expression is critical for triggering the cascade of events leading to a normal immune response. Induction of MHC class II genes by interferon-gamma is characterized by a long lag period (8-12 furs) and total dependence on de novo protein synthesis, suggesting that the induction is mediated by one or more 'early' activators, themselves induced by interferon-gamma. Most recently, Celada et al. (host institution) have cloned the cell type-specific transcription factor ACII (activator of class II) which is induced within 30 minutes after interferon-gamma stimulation, without de novo protein synthesis. ACII belongs to the basic helix-loophelix family of proteins and contains 3 leucine-rich repeat regions which are thought to be involved in protein-protein interactions. In addition, B lymphocytes from patients suffering from a combined immunodeficiency lack 2 of the 4 protein isotypes of ACII normally expressed in humans, thus suggesting that ACII may act as a master-regulator of the interferon-gamma-induced signal transduction pathway that results in a normal immune response. Since ACII is an early response gene, we propose to study (1) the regulation of
interferon-gamma-induced expression of ACII, (2) biological functions of ACII, and to identify (3) ACII interacting partner proteins. The innovative aspect of this study is to characterize the modulation and function of an apparent master-regulator of the interferon-gamma-mediated immune response.
Training content (objective, benefit, expected impact)
As I have a background in molecular haematology, I wish to specialize in molecular immunology. The host institution offers an excellent educational Master Program in Immunology thoroughly covering theoretical immunology. I will benefit from the practical training by learning methods that deal with molecular immunology, promoter regulation and protein-protein interactions. Applying these methods in projects which I shall pursue by myself in the future will have a significant impact on my scientific career.
Industrial relevance
To reveal the intracellular checkpoints of the regulation of MHC class II gene expression is of critical medical relevance in order to identify drugs that manipulate or repress the expression of class II genes, e.g. to overcome transplantation problems and a autoimmunity..


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