Project description
Dissecting intestinal immune cell regulation
The intestinal tract is a dynamic environment responsible for nutrient absorption and is constantly being exposed to microbes and dietary antigens. Intestinal homeostasis is maintained by the immune system which balances protective inflammatory responses against pathogens with tolerance to commensal bacteria and food-derived molecules. However, the underlying mechanisms of how intestinal immune cells are regulated remain poorly understood. The ERC-funded DeconstrucTolerance project aims to delineate the role of regulatory T cells in preventing intestinal inflammation. Researchers will study gene expression regulation and identify transcription factors implicated in the process. Overall, the project has the potential to uncover new insights into intestinal immune regulation.
Objective
The intestinal tract is the main site of nutrient absorption and faces constant exposure to complex environmental stimuli. Intestinal barrier integrity and functionality are safeguarded by the intestinal immune system, which must balance its pro- and anti-inflammatory activities to provide protection from pathogenic microorganisms while preventing unwanted reactivity to self-antigens, commensal microbes, and dietary components. The intestinal immune environment can be viewed as a multicellular network in which the identity and function of individual cells is intrinsically programmed by transcription factors (TFs) that regulate their gene expression. These cells in turn can respond to signals in their environment and impact the behavior of their neighbors, which over time drives changes in tissue physiology. Conventional genetic knockout approaches offer insufficient temporal resolution to dissect these regulatory layers.
In this proposal, we will employ chemical genetic protein degradation using the auxin-inducible degron 2 (AID2) system to deconstruct the intestinal immune regulatory network. These studies will focus on the role of Foxp3+ regulatory T (Treg) cells, whose continuous immunosuppressive activity is required to prevent the onset of intestinal inflammation. In Aim 1, we will use newly generated mouse models to probe the direct gene regulatory functions of key TFs that define intestinal Treg cell subsets. In Aim 2, we will fluorescently label intestinal Treg cells and rapidly degrade the TFs that confer their suppressive activity to study their functionality in situ. Finally, in Aim 3, we will use a reversible mosaic protein degradation strategy to study how the signals that precede and promote intestinal Treg cell differentiation shape the developing intestinal immune system. Together, these studies will provide fundamentally new insights into the regulatory network underlying intestinal immune tolerance.
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 physiology
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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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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.
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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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1030 Wien
Austria
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