SubsidieMeestersDeconstructing Intestinal Immune Tolerance
This project aims to dissect the intestinal immune regulatory network using chemical genetic protein degradation to understand the role of Foxp3+ Treg cells in maintaining immune tolerance.
Projectdetails
Introduction
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.
Immune Environment
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.
Limitations of Current Approaches
Conventional genetic knockout approaches offer insufficient temporal resolution to dissect these regulatory layers.
Proposal Overview
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.
Specific Aims
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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.
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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.
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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.
Conclusion
Together, these studies will provide fundamentally new insights into the regulatory network underlying intestinal immune tolerance.
Financiële details & Tijdlijn
Financiële details
| Subsidiebedrag | € 1.500.000 |
| Totale projectbegroting | € 1.500.000 |
Tijdlijn
| Startdatum | 1-1-2024 |
| Einddatum | 31-12-2028 |
| Subsidiejaar | 2024 |
Partners & Locaties
Projectpartners
- FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBHpenvoerder
Land(en)
Vergelijkbare projecten binnen European Research Council
| Project | Regeling | Bedrag | Jaar | Actie |
|---|---|---|---|---|
T cell regulation by fed state bacterial metabolitesThis project aims to identify immunoregulatory bacterial molecules produced in response to food intake, enhancing understanding of gut microbiome tolerance mechanisms and their impact on intestinal health. | ERC Starting... | € 1.499.548 | 2024 | Details |
Deciphering Antigen-Specific Circuits Orchestrating Tolerance.This project aims to uncover the cellular interactions governing peripheral regulatory T cell responses to gut microbes, enhancing understanding of tolerance mechanisms for treating inflammation-related conditions. | ERC Starting... | € 2.175.000 | 2024 | Details |
Innate lymphoid cells and tissue adaptation to changing metabolic needsThis project aims to elucidate the role of ILC3 and the IL-22:IL-22BP module in intestinal adaptation to metabolic changes, with implications for understanding and treating metabolic diseases. | ERC Advanced... | € 2.379.266 | 2022 | Details |
Engineered symbionts elucidate gut T cell memory and its (dys)regulationThe GuT Memory project aims to uncover the mechanisms of microbiota-directed Th cell memory to enhance vaccine design and target pathogenic T cells in inflammatory bowel disease. | ERC Starting... | € 1.600.683 | 2024 | Details |
Microbiota-controlled trafficking of immunosuppressive intestinal T cells into cancerThis project aims to uncover the mechanisms by which intestinal microbiota influences immune checkpoint blockade resistance in cancer through MAdCAM-1 regulation and T cell dynamics. | ERC Advanced... | € 2.487.834 | 2024 | Details |
T cell regulation by fed state bacterial metabolites
This project aims to identify immunoregulatory bacterial molecules produced in response to food intake, enhancing understanding of gut microbiome tolerance mechanisms and their impact on intestinal health.
Deciphering Antigen-Specific Circuits Orchestrating Tolerance.
This project aims to uncover the cellular interactions governing peripheral regulatory T cell responses to gut microbes, enhancing understanding of tolerance mechanisms for treating inflammation-related conditions.
Innate lymphoid cells and tissue adaptation to changing metabolic needs
This project aims to elucidate the role of ILC3 and the IL-22:IL-22BP module in intestinal adaptation to metabolic changes, with implications for understanding and treating metabolic diseases.
Engineered symbionts elucidate gut T cell memory and its (dys)regulation
The GuT Memory project aims to uncover the mechanisms of microbiota-directed Th cell memory to enhance vaccine design and target pathogenic T cells in inflammatory bowel disease.
Microbiota-controlled trafficking of immunosuppressive intestinal T cells into cancer
This project aims to uncover the mechanisms by which intestinal microbiota influences immune checkpoint blockade resistance in cancer through MAdCAM-1 regulation and T cell dynamics.