Functional genomics.

Connective tissue disease (CTD) refers to a large and diverse group of disorders affecting the protein-rich tissues that support our body's organ systems. Patients most typically present with skin, spinal cord, eye, heart, blood vessel and/or skeletal manifestations. CTDs can either be inherited or provoked by environmental factors. With respect to hereditary CTD, an increasing number of genetic causes has been discovered over the past ten years owing to the advent of high-throughput DNA sequencing technologies. In-depth investigation of these defects' molecular mode of action at the cellular and tissue level is now increasingly needed in order to complete the mechanistic CTD puzzles and to facilitate the development of novel drug therapies. I will establish a research group that aims to address these CTD needs, with a primary focus on thoracic aortic aneurysm and dissection (TAAD) and skeletal dysplasia. TAAD denotes an abnormal widening and/or rupture of the largest human artery, i.e. the aorta, and entails a high risk for sudden death due to severe internal bleeding. It is estimated to account for 1-2% of all deaths in the Western population. Skeletal dysplasias are a group of more than 200 disorders that affect bone and cartilage growth, resulting in abnormal skeleton shape and size. At first glance, these two conditions might seem oddly dissimilar. From a molecular point of view they have quite a lot in common though. Different defects in a set of genes have been shown to cause both TAAD and skeletal dysplasia. Moreover, significant overlap exists with regard to the yet described dysregulated subcellular processes. By comprehensively studying the entire disease continuum, I will contribute synergistically to a better understanding of the disease mechanisms and, hence, the treatment of both separate clinical entities. Three major strategic research pillars have been defined on which I desire to concentrate: (1) identification of the DNA variants that explain why some subjects carrying a certain disease-causing genetic defect are more severely affected than others with that identical defect (i.e. modifier variants); (2) elucidation of the molecular mode of action of disease-causing and disease-modifying genetic variants; and (3) discovery of novel disease-remedying drug compounds as well as the genetic determinants that explain variation in drug response between patients. The experimental set-up will be determined in a project-by-project manner, but will typically involve high-throughput DNA, RNA and/or protein analyses (-omics) as well as classical molecular biology strategies in relevant mouse and induced pluripotent stem cell (iPSC)-derived models. IPSCs are somatic cells (e.g. from skin or blood) that have been reprogrammed to pluripotent cells, and can be differentiated into virtually any cell type of interest. Patient- and control-derived iPSC-vascular smooth muscle cells and iPSC-chondrocytes will be used (i.e. relevant TAAD and skeletal dysplasia cell types, respectively) because of limited access to their native counterparts.

Keywords:MOUSE MODELS, MODEL SYSTEMS, MATRIX COMPONENTS, CARTILAGE

Disciplines:Molecular and cell biology not elsewhere classified