Project description
T cells in neurodegeneration
Neurodegenerative diseases involve the progressive degeneration of neurons, yet the underlying aetiology is incompletely understood. Funded by the European Research Council, the C9-T Immunity project aims to delineate the role of T cells in amyotrophic lateral sclerosis and frontotemporal dementia. These diseases share a genetic mutation in a specific gene which leads to abnormal expansion of a hexanucleotide repeat sequence. This expansion results in the production of repeated RNA sequences with toxic effects on neurons. C9-T Immunity researchers wish to unveil the synergistic effect of peripheral antigen-presenting cells and microglia in these two diseases and potentially identify new biomarkers and therapeutic targets.
Objective
Neurodegenerative diseases are the top 3 leading causes of death and are viewed now as systemic diseases. Adaptive immunity including a T-cell response in the central nervous system (CNS) likely contributes to disease pathogenesis. How T cells are primed and recruited to CNS is largely unexplored, due to the complexity of the process and lack of tools and animal models. I will study these questions on the most common genetic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, a GGGGCC repeat expansion in the C9orf72 gene causes haploinsufficiency through reduced C9orf72 protein expression, and gain-of-function toxicities through repeat RNA and its translation to aggregating dipeptide repeats (DPRs). A synergistic role of these pathomechanisms is suspected but not clearly identified.
I propose that T cells are the missing piece of the puzzle for the synergistic effects of C9orf72 haploinsufficiency and DRP toxicity and will explore a) whether peripheral antigen-presenting cells (APCs) and CNS microglia present DPRs to prime antigen-specific T-cell response; b) whether C9orf72 haploinsufficiency alters antigen presentation of microglia and APCs; c) whether T cells mediate synergic effects of C9orf72 haploinsufficiency and DRP toxicity.
This novel project for the first time addresses peripheral and CNS activation of T cells against DPRs in C9orf72 ALS/FTD and reveals novel mechanism on synergistic effect of C9orf72 haploinsufficiency and DPR toxicity. It offers a unique integration of neurobiological tools, immunological methods, and single-cell-level approaches. It brings solid evidence on the antigen presentation of endogenous aggregating protein to drive antigen-specific T-cell response, which will broad the understanding on ALS/FTD and other neurodegenerative diseases. It presents a promising research trajectory for the identification of new biomarkers, breakthrough therapeutic targets and the development of novel interventions.
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 biochemistry biomolecules proteins
- medical and health sciences basic medicine neurology dementia
- natural sciences biological sciences genetics RNA
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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.1.1 - 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.
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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-2023-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.
53127 BONN
Germany
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