Negative Regulation of Inflammatory Responses Revealed with Camelid Nanobodies
The project aims to develop new cell biology tools to uncover intricate signaling networks that downregulate inflammation, focusing on the roles of NLRC3 and NLRX1 in controlling pro-inflammatory responses.
Projectdetails
Introduction
The innate immune system evokes inflammation to control pathogens or damage. Sophisticated mechanisms interpret molecular triggers to activate inflammasomes or transcription of pro-inflammatory genes. While numerous autoinflammatory conditions underline the need to control inflammation, we still rely on simplistic models to understand its negative regulation.
Hypothesis
I hypothesize that an intricate signaling network interprets information to prevent or downregulate inflammation. Understanding these so far elusive processes demands radically new cell biology tools, which I will develop and apply in ‘DEFLAMMATION’.
Objectives
I propose to define signaling hubs that integrate cellular input and coordinate effectors to actively downregulate inflammation where beneficial to the organism. To yield unprecedented molecular insights, we will apply:
- Nanobodies to inhibit protein function
- Manipulation of post-translation modifications
- Visualization of endogenous proteins and their binary interactions
I hypothesize that two poorly understood members of the NLR family, NLRC3 and NLRX1, act as signaling hubs that coordinate negative regulation of pro-inflammatory gene expression. No such coordinator is known for inflammasomes.
Objective 1
In objective 1, we will pinpoint how NLRC3 controls inflammation and T cell activity. I hypothesize that NLRC3 forms anti-inflammatory signalosomes to control the ubiquitination status of pro-inflammatory signaling components.
Objective 2
In objective 2, we will reveal how NLRX1 counteracts interferon responses, inflammation, and proliferation. We will explore whether NLRX1 activation coordinates organelle-specific autophagy to remove pro-inflammatory signaling complexes.
Objective 3
In objective 3, we will identify novel regulatory circuits that control inflammasome activation using CRISPR/Cas9 and cDNA screens, taking advantage of a novel reporter we have developed.
Anticipated Results
The anticipated results will reveal entirely new layers of regulation of inflammation with implications for therapeutic intervention.
Financiële details & Tijdlijn
Financiële details
Subsidiebedrag | € 1.997.828 |
Totale projectbegroting | € 1.997.828 |
Tijdlijn
Startdatum | 1-9-2024 |
Einddatum | 31-8-2029 |
Subsidiejaar | 2024 |
Partners & Locaties
Projectpartners
- UNIVERSITATSKLINIKUM BONNpenvoerder
Land(en)
Vergelijkbare projecten binnen European Research Council
Project | Regeling | Bedrag | Jaar | Actie |
---|---|---|---|---|
Architecture of Peripheral Neuroimmune Circuits and SynapsesThis project aims to explore neuro-ILC2 interactions in vivo using innovative labelling tools to enhance understanding of neuroimmune dynamics and their implications for tissue health and disease. | ERC Advanced... | € 3.500.000 | 2024 | Details |
Spatio-temporal integration of skin inflammationThe project aims to elucidate spatio-temporal inflammasome signaling in keratinocytes to identify new therapeutic targets for inflammatory skin disorders like atopic dermatitis and psoriasis. | ERC Advanced... | € 2.499.188 | 2023 | Details |
Exploring inflammasome activation and targeted inhibitionThis project aims to elucidate the activation mechanisms of NLRP3 inflammasomes and develop specific inhibitors to advance targeted anti-inflammatory therapies. | ERC Advanced... | € 2.155.047 | 2024 | Details |
Allosteric modulation of immune checkpoint complexes as a new mode of therapeutic intervention in immunotherapyThe project aims to develop novel Nanobodies as safe and effective modulators of immune checkpoint complexes for cancer and autoimmune diseases, potentially outperforming current therapies. | ERC Advanced... | € 2.499.674 | 2024 | Details |
Molecular and Functional Characterisation of Z-nucleic Acid-induced SignallingThis project aims to elucidate the mechanisms of ZBP1 activation by Z-nucleic acids to inform therapeutic strategies for modulating immune responses in autoinflammation, antiviral, and anticancer contexts. | ERC Consolid... | € 1.983.531 | 2024 | Details |
Architecture of Peripheral Neuroimmune Circuits and Synapses
This project aims to explore neuro-ILC2 interactions in vivo using innovative labelling tools to enhance understanding of neuroimmune dynamics and their implications for tissue health and disease.
Spatio-temporal integration of skin inflammation
The project aims to elucidate spatio-temporal inflammasome signaling in keratinocytes to identify new therapeutic targets for inflammatory skin disorders like atopic dermatitis and psoriasis.
Exploring inflammasome activation and targeted inhibition
This project aims to elucidate the activation mechanisms of NLRP3 inflammasomes and develop specific inhibitors to advance targeted anti-inflammatory therapies.
Allosteric modulation of immune checkpoint complexes as a new mode of therapeutic intervention in immunotherapy
The project aims to develop novel Nanobodies as safe and effective modulators of immune checkpoint complexes for cancer and autoimmune diseases, potentially outperforming current therapies.
Molecular and Functional Characterisation of Z-nucleic Acid-induced Signalling
This project aims to elucidate the mechanisms of ZBP1 activation by Z-nucleic acids to inform therapeutic strategies for modulating immune responses in autoinflammation, antiviral, and anticancer contexts.