Increasing age causes progressive deterioration of tissues and organs, leading to impaired tissue function, increased organismal vulnerability to infection, and death. Hence ageing is recognized as a prime disease factor. Improving health in the elderly will be crucial to deal with the enormous socio-economic challenges arising as a consequence of increased life expectancy.
Membranes are at the center of cellular biology, compartmentalizing cells into functional distinct sub-compartments and constituting scaffolds for signal initiation and propagation. Hence, it is not surprising that deregulated membrane trafficking emerges also as key processes in ageing and disease. By combining model organisms, such as C.elegans and mouse, with mammalian cell culture, advanced molecular biology and protein biochemistry, and ‘omics’ approaches we aim at characterizing deregulated membrane trafficking in ageing and disease. This will allow a functional understanding of underlying biological processes which can be employed to design strategies promoting healthy ageing.
Our goal is to decipher causative molecular mechanisms being deregulated in ageing and disease and involved in perturbed membrane trafficking focusing on autophagy. In Aim 1 (Aktories) we will study the trafficking of bacterial toxins and will use these toxins as tools to decipher the influence of the cytoskeleton and Rho GTPases on autophagosomal vesicle trafficking. Aim 2 (Dengjel) addresses the crosstalk of retrograde Golgi/ER vesicle and autophagosome trafficking by proteomics approaches and its deregulation in ageing. Aim 3 (Eimer) employs the nematode Caenorhabditis elegans to study the function of Rab GTPases in mitophagy. Using electron microscopy the function of a subset of Rab GTPases will be investigated. In Aim 4 (Huber) the autophagosomal-mitochondrial crosstalk is studied in kidney ageing using mouse genetics, optical markers and proteomics. Molecular targets identified in the specific aims will be investigated by the other researchers on their functions in the respective model systems. Thus, by using discrete biological and technical approaches we will comprehensively study vesicular trafficking mechanisms and their regulation in physiology and pathology.