Using the endothelial-enriched proteome to identify new mechanisms and biomarkers for cardiovascular disease

Bakgrund: The importance of endothelial cells (EC) in cardiovascular disease (CVD) is undisputed, but understanding of underlying mechanisms is limited. As part of our previous Hjärt Lungfonden project grant, we generated the first description of the core EC-enriched transcriptome, and used this dataset to cross check GWAS and proteomics data from CVD case control patient cohorts, to identify EC-genes/proteins with CVD associations.

We are studying the function of a number of these EC-enriched genes, and have revealed previously unknown roles in haemostasis. Our other focus was to perform a discovery study to analyse EC-derived proteins in plasma from the Swedish CArdioPulmonary bioImage Study (SCAPIS) pilot; we identified CVD risk associated EC-derived proteins and demonstrated that they have potential for risk prediction.

Målsättning: (i) To develop cutting edge quantification assays for the measurement of EC-derived plasma protein biomarkers identified as associated with CVD risk in the SCAPIS pilot discovery, to use for quantification in an expanded sample set from SCAPIS and a replication cohort. (ii) To perform functional investigations of CVD-associated EC genes, including continuation of studies initiated in the previously funded proposal. (iii) To perform further discovery screening to measure panels of inflammation-related and tissue-specific EC-derived proteins in SCAPIS pilot.

Arbetsplan: We will verify results from the discovery screen of SCAPIS pilot, using dual-binder immunoassays or a mass spectrometry-based method for multiplex detection. These assays will be used to verify targets and quantify levels in a larger sample set from SCAPIS (n=5000) and a replication cohort from Norway (n=5000). We will continue to investigate the function of EC-enriched CVD-associated proteins, including role in growth, survival, angiogenesis, inflammation and thrombosis/coagulation, using specialised in vitro assays and genetic modifications.

Selected candidates will be investigated using mouse models of CVD. Discovery screening of the new candidates in SCAPIS pilot will be done with single-binder affinity assays (relative quantification).

Betydelse: In a future perspective, two outcomes could lead to improvements in health care: (1) Identification of EC dysfunction mechanisms to provide targets for pharmacological treatment/risk reduction, and (2) Identification of EC-derived plasma biomarkers for CVD risk prediction, diagnosis, or prognosis purposes.