Supervisor: dr hab. Patrycja Kaczara

Jagiellonian Centre for Experimental Therapeutics

Project description:

Thrombosis, which is associated with various cardiovascular diseases, is one of the leading clinical concerns associated with high morbidity and mortality. Importantly, blood platelets in patients with metabolic diseases often exhibit hyperreactivity, leading to an increased risk of cardiovascular events related to thrombosis. Despite antithrombotic treatment, the risk of such events is not eliminated; furthermore, unwanted side effects, such as bleeding, may occur. Platelet aggregation is an energy-demanding process that can be supported by ATP provided by both glycolysis and mitochondrial respiration [1, 2]. Most commonly used antiplatelet drugs are directed toward targets that do not affect energy metabolism, therefore current antiplatelet strategies may not provide optimal inhibition of platelet hyperreactivity. It is known that beyond ATP production, cellular metabolism controls the fate of cells. However, it is not yet clear how the imbalance between the cytosolic and mitochondrial energy metabolism processes affects the activity of blood platelets.

The central hypothesis of the project is that reprogramming platelet energy metabolism enhances the action of selected antiplatelet drugs under the conditions of hyperglycaemia and atherosclerosis. The aim of the project is to explore the metabolic processes responsible for the development of platelet hyperreactivity and to investigate how combined treatment with selected antiplatelet drugs and metabolic inhibitors affects platelet energy metabolism and activity. Pharmacological modulation of metabolic pathways will be a tool for observing changes at the molecular, organellar and cellular levels by analysing metabolic fluxes, ROS and calcium signaling, mitochondrial quality control, and platelet function. The results of the project are expected to identify new metabolic targets for the development of innovative antiplatelet therapies that protect against or decrease thrombosis.

References:

[1] Kaczara et al. “Antiplatelet effect of carbon monoxide is mediated by NAD+ and ATP depletion” Arteeriosclerosis, Thrombosis, and Vascular Biology 2020; 40:2376-2390

[2] Flora et al. “Metabolic targeting of platelets to combat thrombosis: down of a new paradigm?” Cardiovascular Research, 2023; 119:2497-2507

Scope of work:

Basic Focus: Examination of activity, aggregatory potential and energy metabolism of blood platelets.

• Design, prepare and conduct experiments on isolated blood platelets in vitro.
• Conducting functional in vitro assays for analysis of platelet activation, aggregation, and energy metabolism.
• Investigation of interactions between antiplatelet drugs and inhibitors of energy metabolism pathways.

Objective: Improve the understanding of the crosstalk between platelet reactivity and energy metabolism.

Required professional qualifications:

• The PhD student must hold Master's degree in Life Sciences discipline.
• The selected candidate should have practical laboratory experience, supported by references of the academic tutor and qualifications and suitability for research.
• The PhD students should have very good knowledge of English (written and spoken), be ready to learn new techniques, attending courses and be creative with good and responsible attitude, multitasking approach, and good organizational capacity.