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DeconstrucTolerance

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Deconstructing Intestinal Immune Tolerance

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... see more

31/12/2028

FORSCHUNGSINSTITUT...

2M€

Project Budget: 2M€

Project leader

FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

PARTICIPATION DEPralty Sin fecha límite de participación.

Financing granted El organismo HORIZON EUROPE notifico la concesión del proyecto The day 2024-01-01

ERC-2023-STG: ERC STARTING GRANTS Scope:Objectives

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FORSCHUNGSINSTITUT FUR MOLEK...

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Project duration: 59 months Date Start: 2024-01-01
End date: 2028-12-31

Project leader

FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Project Budget 2M€

participation deadline Sin fecha límite de participación.

Project description 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.

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