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The molecular complexity of the complement system

The complement system is a regulatory pathway in mammalian plasma that enables the host to recognize and clear invading pathogens and altered host cells, while protecting healthy host tissue. This regulatory system consists of ~30... ver más

31/03/2014

2M€

Presupuesto del proyecto: 2M€

Líder del proyecto

UNIVERSITEIT UTRECHT 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 FP7 notifico la concesión del proyecto el día 2014-03-31 No tenemos la información de la convocatoria

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1 Participantes

0.00€ | Lider

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Líder del proyecto

UNIVERSITEIT UTRECHT No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 2M€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto The complement system is a regulatory pathway in mammalian plasma that enables the host to recognize and clear invading pathogens and altered host cells, while protecting healthy host tissue. This regulatory system consists of ~30 large multi-domain plasma and cell-surface proteins, that act in concert through an interplay of proteolysis and complex formations on target membranes. We study the molecular events on membranes that ensure initiation and amplification of the response, protection of host cells and activation of immune responses leading to cell lysis, phagocytosis and B-cell stimulation. In the past few years, we have resolved the structural details of the large complement proteins involved in the central, aspecific labelling and amplification step; with recent data we revealed the structural basis of the assembly and activity of the protease complex associated with this step. These insights into the central aspecific reaction, and the experiences gained on working with these large multi-domain proteins and complexes, give us an excellent starting point to addres the questions of specificity, protection and activation of immune cells. The goal of the proposal is to elucidate the multivalent molecular mechanisms of recognition, regulation and immune cell activation of the complement system on target membranes. We will use protein crystallography and electron microscopy to study the interactions and conformational changes involved in protein complex formation, and (single-molecule) fluorescence to resolve the multivalent molecular events, the conformational states and transitions that occur on the membrane. The combined data will provide mechanistic insights into the specifity of immune clearance by the complement system. Understanding the molecular mechanisms of complement activation and regulation will be instrumental in developing more potent therapeutics to control infections, prevent tissue damage and fight tumours by immunotherapies.

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