Objective
Failure of thymic tolerance may result in severe autoimmune diseases that target the central nervous system (CNS), including Multiple Sclerosis (MS), Myelin Oligodendrocyte Glycoprotein (MOG)-associated Disease (MOGAD), and Neuromyelitis Optica Spectrum Disorders (NMOSD). Recently, we discovered a new layer of thymic tolerance in that thymic B cells get licensed to present activation-induced autoantigens, among them AQP4 (the target antigen in NMOSD). Thymic B cells are necessary and sufficient to purge the T cell repertoire of AQP4-specific clones.
In BREAKING BAD, we will investigate in depth how thymic B cells shape the AQP4-specific T cell repertoire by either deleting AQP4-specific conventional T cells or agonist-selecting Foxp3+ Treg cells. To understand B cell-intrinsic and extrinsic checkpoints of this process, we will use genetic means to disrupt thymic tolerance to AQP4. Since we have cloned a variety of AQP4-specific TCRs, we are now in the position to track fate decisions and functional phenotypes of naïve T cells that react against AQP4, which is – in contrast to MOG – not only expressed in the CNS but also in peripheral organs. Finally, our data indicate that amyloid precursor protein (APP), associated with cerebral amyloid angiopathy and Alzheimer's disease, is an autoantigen that is – very similar to AQP4 – induced in B cells upon CD40 stimulation and expressed in thymic B cells. Therefore, we will investigate the APP-specific T cell repertoire and its ability to provide T cell help for the generation of anti-amyloid Abeta antibodies upon disruption of B cell-mediated tolerance to Abeta peptides by conditional genetic ablation of APP in B cells.
In summary, BREAKING BAD will explore the significance of B cell-mediated tolerance for CNS autoantigens. We anticipate that our experiments will revolutionize the understanding and perhaps potential treatment options of CNS autoimmunity but also of major degenerative disorders like Alzheimer's disease.
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: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- medical and health sciences basic medicine neurology dementia alzheimer
- natural sciences biological sciences biochemistry biomolecules proteins
You need to log in or register to use this function
We are sorry... an unexpected error occurred during execution.
You need to be authenticated. Your session might have expired.
Thank you for your feedback. You will soon receive an email to confirm the submission. If you have selected to be notified about the reporting status, you will also be contacted when the reporting status will change.
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.
-
HORIZON.1.1 - European Research Council (ERC)
MAIN PROGRAMME
See all projects funded under this programme
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-ERC - HORIZON ERC Grants
See all projects funded under this funding scheme
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2024-ADG
See all projects funded under this callHost institution
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.
81675 MUENCHEN
Germany
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.