BreathEASY - Understanding the molecular ballet that starts asthma.

Inflammation is crucial for immunity but can lead to diseases like asthma, arthritis or cancer if uncontrolled. It is regulated by a network of lipid mediators like leukotrienes (LTs).

Produced by leukocytes mostly under stress, LTs like LTA4, LTB4, LTC4 & LTD4 are formed in a biosynthesis cascade started by 5-Lipoxygenase (5LO), with LTB4 being pro-inflammatory and LTC4 & LTD4 linked to asthma. This makes 5LO a target for anti-inflammatory drugs like Zileuton. But many of these drugs have serious side effects. 5LO also produces anti-inflammatory molecules.

Due to its importance, activity of 5LO is well-regulated within cells, with ‘supporting actors’ of LT biosynthesis located in different cell compartments.

Under stress, Coactosin Like Protein (CLP) helps 5LO to move from cytosol to nuclear membrane, where 5LO Activating Protein (FLAP) helps it to start LT biosynthesis.By disrupting 5LO’s interaction with CLP & FLAP (e.g., with new drugs), we may stop LT biosynthesis without affecting the anti-inflammatory role of 5LO.

But for this we need to understand the molecular basis of interaction between these proteins.

With this objective, in BreathEASY, I would develop a direct-observation method to quantify interactions of isolated 5LO with CLP & FLAP, which I would then use to study their interactions in various biochemical conditions.

Moreover, to understand its mechanism of action, I would also strive to solve the atomic structure of the protein complex responsible for initiation of LT biosynthesis.Three impacts are expected from BreathEASY.

By improving our knowledge on inflammation this project would contribute towards UN’s health related SDGs and EU’s mission cancer. It will also allow structure-based drug development. Finally, the developed method can potentially be commercialized to create new drug-screening tools or services. In these ways, BreathEASY is expected to improve the quality of Europe’s R&I, thereby increasing its competitiveness.