Project description
Mitochondrial regulation in leukaemia stem cells
The morphology of mitochondria, the powerhouse organelles of the cell, is driven through a dynamic balance between fusion and division, known as fission. These processes also allow the cell to adapt to its changing energy needs. However, disruption of this balance has been linked to various diseases. With the support of the Marie Skłodowska-Curie Actions programme, the FIAT project is focusing on the mitochondrial membrane protein FIS1, known for its role in apoptosis and the removal of damaged mitochondria. The researchers are interested in the role of FIS1 in acute myeloid leukaemia (AML) and especially in leukaemic stem cells. Results will provide important insight into mitochondrial regulation in AML.
Objective
Mitochondrial morphology is controlled by a set of “mitochondria-shaping” proteins that govern fusion and fission of the organelle. Fission is executed by dynamin-related protein 1 (DRP1) that binds to adaptors on the outer mitochondrial membrane to oligomerize and sever mitochondria. Fission 1 (FIS1) is among the putative mammalian DRP1 adaptors, but it appears dispensable for mitochondrial fission. Conversely, FIS1 seems to participate in the regulation of mitochondrial autophagy (mitophagy), interaction between mitochondria and lysosomes, and apoptosis. Because of these multifunctional roles, FIS1 emerged as an appealing pharmacological target and peptides inhibiting its interaction with DRP1 have been advanced in the experimental treatment of ischemia-reperfusion and of genetic conditions such as Huntington’s disease. More recently, FIS1 was identified as a crucial factor to sustain Leukemia Stem Cells (LSCs) in Acute myeloid leukemia (AML), the second most prevalent and the most fatal leukemia in adult patients. However, our scarce knowledge of the biology of Fis1 is mirrored by the uncertainties on how FIS1 regulates AML LSCs. To close this gap in knowledge, I will take a chemical biology approach and design innovative genetically encoded sensors for FIS1 functions that I will use to identify potential FIS1 small molecules inhibitors. I will then use these chemical probes to evaluate which cellular function of FIS1 is essential for maintenance of AML LSCs. Overall, this project will unveil how a multipronged mitochondrial protein regulates cell pathophysiology and will deliver novel chemical tools to investigate FIS1 function in the context of AML and potentially to evolve into therapies for this hitherto poorly treatable cancer.
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- medical and health sciences basic medicine physiology pathophysiology
- natural sciences biological sciences biochemistry biomolecules
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
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-2024-PF-01
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35122 Padova
Italy
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