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Structural, kinetic, and biophysical analysis and engineering of KIT.METRNL signalling to boost heart tissue regeneration after myocardial infarction

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.

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Topic(s)

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2023-PF-01

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Coordinator

VIB VZW
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 191 760,00
Address
SUZANNE TASSIERSTRAAT 1
9052 ZWIJNAARDE - GENT
Belgium

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Region
Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent
Activity type
Research Organisations
Links
Total cost

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