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OTULINVIVO

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The role of OTULIN and Met1 linked ubiquitin in immune signaling and host defens...

The role of OTULIN and Met1 linked ubiquitin in immune signaling and host defense in vivo The immune system is essential for host defense against infections. Methionine1-linked ‘linear’ ubiquitin chains (Met1-Ub) have emerged as a crucial activator of NF-κB transcription factors, which are vital to immune responses. Re... ver más

31/03/2017

UKRI

183K€

Presupuesto del proyecto: 183K€

Líder del proyecto

UNITED KINGDOM RESEARCH AND INNOVATION No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Fecha límite participación Sin fecha límite de participación.

Financiación concedida El organismo H2020 notifico la concesión del proyecto el día 2017-03-31

MSCA-IF-2014-EF: Marie Skłodowska-Curie Individual F...

I+D

Cerrada hace 10 años

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No hay información privada compartida para este proyecto. Habla con el coordinador.

1 Participantes

UKRI

183.45K€ | Lider

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Duración del proyecto: 24 meses Fecha Inicio: 2015-03-19
Fecha Fin: 2017-03-31

Líder del proyecto

UNITED KINGDOM RESEARCH AND INNOVATION No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 183K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto The immune system is essential for host defense against infections. Methionine1-linked ‘linear’ ubiquitin chains (Met1-Ub) have emerged as a crucial activator of NF-κB transcription factors, which are vital to immune responses. Recent findings suggest that defects in Met1-Ub signaling in humans can lead to severe immune dysfunction and cancer. Met1-Ub is generated by the linear ubiquitin chain assembly complex (LUBAC). Yet, how LUBAC and Met1-Ub signaling are regulated remains elusive. We recently discovered OTULIN, the only deubiquitinase known to specifically disassemble Met1-Ub. OTULIN antagonizes LUBAC and restricts Met1-Ub and NF-κB signaling in cell culture; however, the role of OTULIN and Met1-Ub in immune signaling and host defense in vivo is largely unknown. We have established novel mouse strains with cell type-specific deletion of OTULIN. I will use these mice to explore the in vivo function of OTULIN and Met1-Ub in the innate and adaptive immune responses, and to identify OTULIN substrates in primary cells using state-of-the-art mass spectrometry-based proteomics. I will study OTULIN’s role in immune homeostasis, in response to bacterial infection, and in mounting type-1 and type-2 adaptive immune responses by state-of-the-art methods of immunological analyses including comprehensive multiplex analyses of cytokines. Met1-Ub regulates the acute phase cytokines TNF and IL-6 and may thus control the development of type-1 versus type-2 immune responses. Hence, I will test OTULIN’s role in models of asthma, a disorder characterized by an imbalance between type-1 and type-2 responses. Subsequently, I will analyze immune signaling pathways in primary cells using mass spectrometry-based proteomics to identify OTULIN substrates in specific cell types. This will greatly deepen our understanding of the physiological role of OTULIN and Met1-Ub in the immune response and may provide important insight into human immunological disorders and rationales to treat these.

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