Determining how bioactive phospholipids regulate development of abdominal aortic aneurysm and coagulation using multiomic approaches

Abdominal aortic aneurysm (AAA) is an inflammatory disease with high mortality and limited treatments, associated with dysregulated coagulation and higher bleeding risk during surgery. How signaling lipids regulate AAA development is unknown.

We recently demonstrated that two related sub-classes of bioactive phospholipids (PL), pro-coagulant enzymatically-oxidized PL (eoxPL) and lysophospholipids (lysoPL), may play central roles.

Here we will conduct mechanistic studies in animal models and a human cohort, applying genetics, genomics and lipidomics to address the hypothesis that PL families are endogenous modulators of inflammation and thrombosis during AAA development. First, we will determine how eoxPL regulate anti-coagulation and clot fibrinolysis.

Second, we will map the “coagulotype” and eoxPL/lysoPL signature in mice, determining how clotting is influenced by genetic deletion of eoxPL-generating enzymes during AAA. The impact of modulating eoxPL/FactorXa on AAA-associated inflammation will be determined.

Human cohort tissue analysis (thrombus and AAA tissue) will enable detailed mapping of PL generation and metabolism alongside inflammation.

A therapeutic aim will involve in vivo administration of eoxPL, determining dosing regimens for preventing/potentially reversing AAA in vivo.

Our programme will determine how PL contribute to AAA, providing new mechanistic insights and aiming to develop treatment strategies for a devastating condition with few therapeutic options.