Abstract

Cell death is a physiological process that sustains individual's homeostasis. Millions of cells die every day in response to internal and external stimuli, maintaining a tight balance that promotes human health. The imbalance of these death pathways provokes the appearance of numerous pathologies, such as cancer or neurodegenerative disorders, inflammatory diseases, etc. Despite advances in the molecular understanding of these pathways, the specific and effective modulation of the different types of cell death remains a challenge in biomedicine.

The molecular pathways that regulate cell death are closely linked to cell membranes. While Bcl-2 family proteins control the permeabilisation of the outer mitochondrial membrane in response to apoptotic stimuli, gasdermins and MLKL proteins act as executors promoting proinflammatory cell death by forming pores in the outer membrane in response to pyroptosis and necroptosis stimuli, respectively. In fact, the permeabilisation of these membranes constitutes the point of no return in the processes of death.

Our team brings together experts in the study of membrane proteins and cell death. Building on the basic knowledge generated in our previous projects (PROMETEOII/2014/061; PROMETEO/2019/065), we have developed two new therapeutic strategies with potential application in the modulation of death in disease models: D1 a modulator of BclxL transmembrane interactions (patent application, P202230029) and MM01 a modulator of pyroptosis (patent EP20382237).

In this project we aim:

1. to increase the basic knowledge of the transmembrane interactome;
2. to advance in the preclinical development of MM01 and D1;
3. to generate new therapeutic strategies targeting cell death in the membrane.