Objective
Progressive disability in multiple sclerosis (MS) remains an unmet clinical challenge, largely resistant to current immunomodulatory therapies targeting acute inflammation. AXhaustMS addresses a fundamental gap by investigating astrocytic exhaustion as a novel cellular mechanism underlying chronic progression in autoimmune central nervous system (CNS) inflammation. I hypothesize that astrocytes, key regulators of CNS homeostasis, enter a dysfunctional “exhaustion” state driven by chronic bystander activation, disrupting essential metabolic support networks with neurons, oligodendrocytes, and microglia.
Using the spontaneous opticospinal encephalomyelitis (OSE) mouse model that recapitulates key pathological features of progressive MS, I will comprehensively define the molecular and epigenomic signatures of exhausted astrocytes and their disrupted cellular communication networks across distinct CNS compartments and disease stages (Aim 1). I will then dissect how activation context – bystander versus direct targeting – determines astrocyte fate towards either durable, sensitized states or maladaptive exhaustion leveraging exclusive T cell receptor (TCR) transgenic mouse systems and controlled T cell transfer models (Aim 2). Finally, I will validate the functional impact of exhaustion markers through ex vivo and in vivo clustered regularly interspaced short palindromic repeats (CRISPR)-mediated gene perturbation strategies, testing therapeutic reversibility (Aim 3).
This meticulous approach integrates innovative animal models, state-of-the-art multi-omics, and advanced gene editing to elucidate astrocytic dysfunction as a key driver of progressive MS. AXhaustMS has transformative potential to shift the treatment paradigm from immune suppression to cellular rehabilitation, offering new avenues for therapeutic intervention in MS and related neurodegenerative diseases characterized by chronic glial dysfunction.
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.
- natural sciences biological sciences neurobiology
- medical and health sciences medical biotechnology genetic engineering gene therapy
- medical and health sciences clinical medicine physiotherapy
- medical and health sciences basic medicine neurology multiple sclerosis
- medical and health sciences basic medicine physiology homeostasis
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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)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Topic(s)
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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.
Funding Scheme
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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-ERC - HORIZON ERC Grants
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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) ERC-2026-STG
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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.
81675 Muenchen
Germany
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