HeartRepairKIT · Structural, kinetic, and biophysical analysis and engineering of KIT.METRNL signalling to boost heart tissue regeneration after myocardial infarction
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2024-04-01 → 2026-03-31
- EU contribution
- €191,760
- Participants
- 2
- Scheme
- HORIZON-TMA-MSCA-PF-EF
Lines connect the coordinator with its partners.
Results in brief
Structural, kinetic, and biophysical analysis and engineering of KIT.METRNL signalling to boost heart tissue regeneration after myocardial infarction
Cardiovascular diseases are the leading cause of death worldwide, with millions of patients suffering from long-term complications after heart attacks. One of the major medical challenges is the limited ability of the heart to regenerate damaged tissue, which often results in reduced quality of life and high healthcare costs. Recent scientific discoveries suggested that a protein called meteorin-like (METRNL) might stimulate heart tissue repair by interacting with a receptor called KIT, opening a potential new avenue for therapeutic development. However, the molecular details of this interaction were unknown, limiting its use in medicine. The goal of the HeartRepairKIT project was to understand how KIT signalling towards cardiac regeneration works at the molecular level and to use this knowledge to develop improved protein-based agents that could enhance heart tissue repair. The project combined experimental and computational approaches, including structural biology, biophysics, and artificial intelligence (AI)-based protein design, with the broader aim of contributing to new strategies for cardiovascular therapy.
Data: CORDIS, © European Union
Project objective
KIT, a receptor tyrosine kinase, is dimerized at the cell surface by the cytokine stem cell factor (SCF) to initiate signalling pathways securing fundamental cellular processes, including hematopoiesis, gametogenesis, and melanogenesis. Impaired signalling due to KIT mutations or deficiency leads to various malignancies such as leukemia and melanoma. However, recent data have shown that KIT can also initiate signalling by binding meteorin-like protein (METRNL), triggering unrelated stimulation of heart tissue regeneration. Ischemic heart diseases are the leading cause of mortality and morbidity worldwide, with approximately 9 million annual deaths and over 180 million disability-adjusted life years lost. Therefore, revealing the molecular principles and mechanism of this completely new function of KIT gives hope for new opportunities towards novel therapies that might maximize the efficiency of heart recovery after heart disease incidence. However, the field is currently plagued by a paucity of mechanistic details and the structure-function relationship of the KIT.METRNL complex assembly. The goal of this project is to derive the structure-function landscape of the novel interaction between KIT and METRNL and to provide a blueprint for how KIT can be activated by two structurally distinct protein ligands. The gained knowledge will govern the rational engineering of METRNL towards improving its interaction with KIT to elicit intensified signalling that can lead to amplified heart tissue regeneration. This aim will be achieved by synergistically combining methods of molecular and structural biology (supervisor’s expertise), biomolecular kinetics and rational protein engineering (researcher’s experience), and single molecule biophysics (secondment). Collectively, this research endeavour will impact basic and applied cardiovascular disease research and promises to provide new possibilities for alleviating the enormous socioeconomic burden associated with these diseases.
Original text from CORDIS.
Participants
Links
- View on CORDIS
- DOI: 10.3030/101155448
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e512ef7cf8&appId=PPGMS
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e52df3d841&appId=PPGMS
Data: CORDIS, © European Union