Extracellular ASC Specks as functional inflammasome in cardiovascular disease

• Applicant: Dr. Julian Merz, since 9/2023
• Subject Area: Cardiology, Angiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467077284

Atherosclerosis and its sequelae such as mycardial infarction, stroke, or peripheral artery disease are the main drivers for mortality worldwide. It is well established from basic science that atherosclerosis is a chronic imflammatory disease of the vessel wall. Three years ago the CANTOS trial could show for the first time the efficiacy of an antii-inflammatory therapy im human cardiovascular disease. In this study, patients with residual inflammatory activity were treated with an IL-1beta antibody. IL-1beta is the product of an enzyme cascade, the so called inflammasome, which is activated by several mechanisms such as cholesterol crystals or extracellular ATP within inflammatory active tissue. Recent studies suggest that the activation of the inflammasome induces pyroptosis. However, the inflammasome forms a stable "ASC-Speck" and is released into the extracellular space. From there it can be uptaken by other cells thereby activating the host cell. The role of these mechanisms in the context of cardiovascular disease are unknown and are planned to be investigated in the present project. Following questions are supposed to be answered using animal models and clinical data.1.) How is the inflammsome activated in atherosclerosis? Do extracellular Specks promote inflammation and accumulate in atherosclerotic lesions in vivo? (AP1)2.) Are ASC-Specks detectable in human atherosclerotic lesion? Are they a potential biomarker for coronary artery disease? (AP2)? 3.) Which cells produce ASC Specks and which functions do they promote?

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Peter Stachon, until 9/2023