Strukturelle und funktionelle Analyse ausgewählter High Mobility Group Gene des Haushundes

Abstract

Medical advances due to scientific research made remarkable progress in the past decades fighting cancer. Nevertheless according to the United Nation s World Cancer Report 2008 tumour diseases are the leading cause of death with 7.6 million deaths and 12.4 million the new cancer cases a year. According to cancer the dog as an animal model joins the popular rodent model in order to study and understand the molecular genetics of tumour diseases and to develop new therapeutic strategies against cancer. Canine tumour diseases are distinguished by spontaneous development and dogs and humans share striking similarities in the case of oncology. The main part of this thesis comprises the comparative genomics and tumour biology of the human and canine tumour diseases focusing in particular prostate carcinomas by molecular characterisation of the genes and proteins HMGA1, HMGA2, THADA, RAGE, TNFalpha, and IL-alpha/beta. Genomic characterisations of high evolutionary conserved genes are the fundamentals for functional and structural analysis of tumour relevant genes. According to this principle a gene therapeutic approach was developed in order inhibit the HMGA expression of a canine prostate carcinoma cell line with the help of an adeno-associated virus vector. Furthermore and alternative method with gold nanoparticles was established for efficient transfection of eukaryotic cells. In the context of inflammation and angiogenesis during a tumour disease the canine receptor for advanced glycation end products (RAGE) was analysed. The results showed highly conserved molecular similarities (N.B. ligand-receptor domains) between the human and canine RAGE and its isoforms. In both species an aberrant Expression of cytokines e.g. interleukin-1 (IL-1alpha/beta) and the tumour necrosis factor alpha (TNFalpha) plays an important role during the initiation of immune response and inflammation. In particular during the course of the Langerhans cell histiocytosis (LCH) large quantities of cytokines are produced. Interestingly most clinical and pathological features of the canine malignant histiocytosis resemble those of LCH in humans. Finally dogs could be used as an animal model to elucidate the molecular genetics of malignant histiocytosis as well as LCH. In this connection nucleic base pair substitution within evolutionary conserved gene and amino acid sequences of canine and human cytokines were investigated.