Project Details
Projekt
Development of a transcriptomic cell atlas of atherosclerotic plaque instability - Defining inflammatory pathways and novel therapeutic targets
Applicant
Dr. Lisa Domke
Subject Area
Cardiology, Angiology
Term
from 2022 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517383296
Cardiovascular diseases (CVDs) are a leading cause of death worldwide - ahead of COVID-19 and cancer. Most CVDs are caused by atherosclerosis, a chronic inflammatory disease of the arteries. Currently, even optimally treated patients with atherosclerosis remain at significant risk of major adverse cardiovascular events (MACE) and, despite being a known driver of atherosclerosis, inflammation is not addressed clinically. We simply do not yet know enough about the immune mechanisms that underpin atherosclerotic plaque instability to prevent plaque rupture.In this application, we propose to establish a unique comprehensive murine and human cell atlas of the immune cell heterogeneity in unstable versus stable plaques and their activation status. For this, single cell RNA-sequencing (scRNA-seq) of advanced unstable and stable human atherosclerotic plaque tissue obtained during carotid and femoral endarterectomy will be applied. Critically, and in addition to globally comparing atherosclerosis at these different sites, we will apply Prof. Karlheinz Peter’s discovery of the near-infrared auto-fluorescence (NIRAF) of unstable atherosclerotic plaques. Using the innovative NIRAF approach, we will dissect each sample into unstable and stable regions prior to sequencing. Obtained scRNA-seq data will be validated by multi-colour flow cytometry and immunohistology. In parallel to our human study, our results will be integrated with data from the tandem stenosis (TS) mouse model - a unique mouse model of atherosclerotic plaque instability and rupture which was developed in the laboratory of Prof. Karlheinz Peter. By defining the cellular landscape of these sites stratified into unstable versus stable disease, we aim to pioneer the discovery of collective and cell type specific mechanisms that ultimately drive atherosclerotic plaque destabilisation and rupture. Importantly, we will make the entire dataset publicly available to support the cardiovascular community in obtaining the critical mass required to address residual cardiovascular risk and to advance future high-end projects focusing on the development of unstable, rupture-prone plaques and pathway analyses. By utilizing this novel cell atlas as a discovery tool, we aim to identify novel drug targets for plaque stabilization. By highlighting the key mechanisms, ultimately, this study aims to be a further step towards precision medicine for affected patients and towards novel, highly effective and long sought-after plaque stabilising therapeutics.
DFG Programme
WBP Fellowship
International Connection
Australia
