Background and previous work
AGEs by themselves or through interactions with their receptors have been implicated in the pathophysiology of numerous age-related diseases. Persistent epigenetic modifications, such as histone modifications, can change gene expression and the ageing process. AGE-induced histone modification in mice was found to change with age and as acetylation and AGE modification targets the same amino acid residues a competition for the respective amino acids is possible. We have shown that accumulation of AGEs in the extracellular matrix is associated with cardiovascular dysfunction and is a predictor for the outcome of patients. Soluble AGEs stimulate intracellular pathways like p38MAPK, ERK, p70S6K and the transcription factors AP1 and NF-κB in cardiac fibroblasts and mesangial cells. Airway pollutions like fly ash stimulate intracellular ROS and AGE formation. In lung cancer, RAGE is downregulated and reexpression of RAGE induces an epithelial-like growth of bronchial carcinoma cells on collagen. We have seen that, especially in tumour cells, methylglyoxal-based modifiedproteins accumulate in the nucleus, whereas pentosidine modifications are mainly seen on the cytoskeleton.
As young and proliferating cells mainly get their energy from mitochondrial ATP
generation, while senescent and tumour cells obtain ATP from glycolysis, we want to test the hypothesis that AGE modifications based on dicarbonyls from the metabolism have an impact on epigenetic regulation.
Determination of AGE modifications in the nucleus during ageing and tumourigenesis: Patterns of AGE-modified proteins will be identified in subcellular fractions in proliferating/resting fibroblasts, cancer cells, in normoxia/hypoxia and before and within replicative senescence. The role of dicarbonyls on AGE accumulation in the nucleus will be proven and modified nuclear proteins will be characterised using MS technology. The modified amino acids will be identified (collaboration with SP1, SP5) and the in-vivo relevance tested in ageing mouse models. Cellular characterisation of the role of the identified proteins: Depending on the proteins identified, their role in cell signalling, gene transcription / translation and regulation will be analysed (collaboration with SP4, SP6, SP9, SP10, SP13 and SP14). Molecular consequence of AGE modification: The effect of protein modification on protein function and structure will be analysed by structural biology methods including NMR spectroscopy (collaboration with SP12).
Prof. Dr. Andreas Simm
Martin Luther University Halle-Wittenberg
Clinic for Heart and Thoracic Surgery
University Hospital Halle
Ernst-Grube Str. 40
06120 Halle (Saale)
Email: Andreas Simm