Dr. rer. nat. Robin Alexander Pilz
The focus of our research group lies on cerebral cavernous malformations (CCM) which are sometimes also called cavernous angiomas or cavernomas. These enlarged endothelial channels can be found in the venous-capillary bed of the central nervous system. They lack supporting pericytes and smooth muscle cells and tend to bleed. Haemorrhages into the neighbouring brain parenchyma may cause recurrent headaches, seizures and stroke-like symptoms.
CCMs may occur sporadically or in an autosomal dominant form. Familial CCM is caused by loss-of-function germline variants in one of three genes: CCM1/KRIT1, CCM2/OSM and CCM3/PDCD10. The prevalence of symptomatic carriers of a pathogenic CCM1, CCM2 or CCM3 variant is approximately 1:5,400-1:6,200. The first symptoms are usually reported in the second to fifth decade of life. However, one third of CCM patients are minors and 20% are younger than 10 years. Analyses of human CCM tissue samples with ultra-sensitive next generation sequencing technologies and immunohistochemistry have supported the hypothesis of a genetic two-hit mechanism in CCM formation (Figure).
We pursue the scientific concept of elucidating the pathogenesis of hereditary vascular malformations at the gene, cell or organism level. For this purpose , we use latest sequencing technologies (long read sequencing) and CRISPR/Cas9-mediated genome editing. By targeted inactivation of CCM1, CCM2 or CCM3 in human induced pluripotent stem cells (hiPSCs) and their differentiation into endothelial cells or three-dimensional blood vessel organoids, we try to mimic the situation in cavernomas as closely as possible.
By combining these complex cell culture models with live cell imaging, compound library screening and bulk and single cell RNA sequencing, we have already gained new insights into cerebral cavernous malformations. For example, we have been able to further characterise the survival advantage of cells following inactivation of CCM1, CCM2 or CCM3 (Figure). This already allowed us to identify pharmacological compounds as new potential therapeutics.
Prof. Dr. Ute Felbor
Dr. Robin Pilz
Dr. Dariush Skowronek
Dr. Christiane Much
Valeriia Saenko, M. Sc. (PhD student)
Till Page (MD student)
Barbara Sendtner (MD student)
