Molecular Pathogenesis
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Injection of a DNA-solution into a pronucleus of a fertilized mouse oocyte

The professorship for Molecular Pathogenesis of the Faculty of Veterinary Medicine was established in 2003 within the Center for Biotechnology and Biomedicine (BBZ) at the Universität Leipzig. It is dedicated to basic and applied research in the field of biomedicine.

The number of identified genetic polymorphisms linked to susceptibility to diseases is steadily increasing in the wake of the completion of the human genome project. In addition, completion of the mouse genome project in conjunction with the availability of tools for precise genetic modification enables a functional analysis of these disease-linked alterations in a mammalian model organism. We are mainly studying the effects of cytokine and cytokine signalling mutations in the context of inflammatory diseases, infections and malignancies. Central subjects of our research include the cytokine Transforming Growth Factor-beta (TGF-beta), Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Interleukins (IL) crucial for distinct types of immune responses (Th1 versus Th2).

TGF-beta is a highly pleiotropic cytokine displaying different activities dependent on cell-type, developmental stage, differentiation and cell cycle position of the target cell. Depending on these parameters, TGF-beta modulates proliferation, apoptosis, activation and differentiation of the respective target cells. Prominent activities include (i) inhibition of epithelial cell proliferation, (ii) stimulation of fibroblast extracellular matrix synthesis, (iii) angiogenesis, (iv) protection of early thymic T-cells from apoptosis and (v) suppression of mature T-cells and macrophages. Due to this broad spectrum of activities, TGF-beta is a central player in regeneration, immune responses and tumorigenesis. By selectively interfering with TGF-beta activity or signalling in genetically engineered mice we are mimicking in these animal models pathological processes observed in patients. In addition, upstream regulators of TGF-beta signalling such as transcription factors of the ets-family are being analyzed in genetically altered animals. The cell-type specificity of our approach may allow for the identification of cell-type specific TGF-beta target genes as targets for diagnostic or therapeutic use.

GM-CSF is a cytokine regulating proliferation, differentiation and apoptosis of hematopoetic cells. In regard to skin, GM-CSF is particularly important for the generation and maturation of epidermal Langerhans cells (LCs) as well as the survival of macrophages. Besides hematopoetic cells, other cell types including keratinocytes have been identified both as sources and as targets for GM-CSF. The release of this cytokine by keratinocytes is triggered by disturbances in skin homeostasis like wounding or tumor promotion. Since GM-CSF has been shown to stimulate keratinocyte proliferation as well as immune cell proliferation and maturation it had been proposed to mediate both, the proliferative burst in keratinocytes as well as inflammation following disturbances of the homeostasis in the skin. We established transgenic mouse models allowing both skin-specific up- and down-regulation of GM-CSF activity. Wound healing and tumorigenesis was significantly altered. Specific target genes have been identified and will be analyzed for their potential in the treatment of wound healing disorders and malignancies.

TH1 and TH2 responses are mediated by specific cytokines. While members of the IL-12 family elicit strong TH1 responses, IL-4, IL-13 and TGF-beta are typical TH2 cytokines. Depending on the infectious agent, the decision between TH1 and TH2 responses is crucial in respect to pathogen elimination and survival. Cryptococcus neoformans is an opportunistic human pathogenic yeast that causes severe diseases in AIDS patients, especially meningitis and meningoencephalitis. A cellular immune response (TH1) is necessary for control of the infection. We analyse the influence of the TH2 cytokines TGF-beta, IL-4 and IL-13 in the pathogenesis in cryptococcosis with cell type specific transgenic and knock out mice.

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Imprint, Last update: 09/27/2007