Epigenetic regulation of plaque progression and instability in atherosclerotic stenosis of the extracranial carotid artery

• Applicants: Privatdozent Dr.-Ing. Jaroslav Pelisek; Professorin Dr. Alma Zernecke-Madsen
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 324512716

Epigenetic mechanisms play an important role in the regulation of gene expression at the chromatin level and can for example significantly contribute to carcinogenesis. Recent studies and our own preliminary work indicate that epigenetics can be of importance also within the scope of atherogenesis, plaque progression and plaque vulnerability. Any systematic research in this area is however still missing.The aim of the submitted scientific project is the systematic investigation of DNA and histone methylation in different stages of atherosclerosis of extracranial internal carotid artery and in the individual cells within the plaque tissue (e.g. smooth muscle cells, monocytes/macrophages, lymphocytes). Furthermore, ex vivo analyses shall be performed on human tissue samples and in vitro in primary cells, to investigate functional relationships and relevant epigenetic factors contributing to plaque progression and vulnerability. For this purpose we dispose of an own large biobank with over 900 carotid plaque specimens including clinical data and patients characteristics. In particular, DNA methylation of specific gene/promoter regions contributing to the atherosclerotic lesion development and progression, which are accessible to epigenetic modification, as well as histone methylations and expression of corresponding methyltransferases and demethylases, shall be analysed. Our findings will be compared with the plaque vulnerability and neurological symptomatology of the patients to detect potential predictors/risk factors of stroke. For the purposes of the project, molecular-biological methods, immunohistochemistry, microdissection, RNA in-situ-hybridisation and siRNA mediated gene silencing shall be applied. We hope to identify with this study novel molecular predictors of increased plaque vulnerability and the risk involved in carotid-mediated ischemic stroke.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Hans-Henning Eckstein (†)