Objective
Psychiatric disorders such as major depression, bipolar disorder, schizophrenia, and autism are highly prevalent chronic diseases. However, their underlying pathophysiology is still largely unknown. Genomic studies have identified single nucleotide polymorphisms (SNPs) in the CACNA1C gene that are robustly associated with all of these major psychoses. Among these is the main non-coding risk SNP rs1006737. Beyond that, a gain-of-function mutation in CACNA1C has been described, which causes a multiorgan phenotype including severe cardiac arrhythmias, immune deficiency, cognitive abnormalities, and autism, named Timothy syndrome (TS). Immune alterations plus the involvement of their primary mediators in the brain, the microglia, have also been reported for psychiatric disorders. Based on this, we aim to introduce the risk A-allele of the CACNA1C SNP rs1006737 as well as the TS mutation G406R into human iPSC control lines using CRISPR base editing. The generated isogenic lines are then differentiated into iPSC-derived microglia cells (iMGs) and undergo a systematic functional characterization, including the analysis of transcriptomic profile, intracellular calcium levels, motility, phagocytic activity, cytokine release, cellular bioenergetics, and mitochondrial parameters. Furthermore, the newly created iMG cultures are tested in brain organoid systems to assess their effects on neuronal activity and function via multielectrode array recordings and single nuclei sequencing. The obtained results will contribute significantly to elucidating whether microglial function is causally affected by the selected CACNA1C risk variants, what underlying checkpoint mechanisms are involved, and whether these changes compromise microglia-neuron interactions, thereby impairing neuronal activity and function. Overall, this study will add to a better understanding of the role microglia play in the pathogenesis and/or progression of CACNA1C-associated psychiatric disorders.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences clinical medicine cardiology cardiovascular diseases cardiac arrhythmia
- medical and health sciences basic medicine physiology pathophysiology
- natural sciences chemical sciences inorganic chemistry alkaline earth metals
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine psychiatry schizophrenia
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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)
MAIN PROGRAMME
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Topic(s)
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.
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.
Funding Scheme
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.
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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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) HORIZON-MSCA-2022-PF-01
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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.
70211 KUOPIO
Finland
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.