Projeto nº: 029910

Referência do Projeto: PTDC/BIA-MIC/29910/2017 (POCI-01-0145-FEDER-029910)

Título: Caracterização estrutural e funcional de toxinas AB que têm como alvo células apresentadoras de antigénios e sua aplicação como vacinas contra cancro

Montante envolvido:

Investimento total: 235.831,17 €

IBMC-Instituto de Biologia Molecular e Celular – 235.831,17€

Apoio FEDER: 200.456,49€

Apoio OE: 35.374,68€

Localização do projeto: Porto, Portugal

Síntese do projeto:

Toxins are virulence factors with extraordinary potency and specificity, often being lethal to cells or inducing significant functional changes. The modular structure of a class of toxins, termed AB toxins, composed of an A domain with catalytic functions, and a B domain capable of translocating the catalytic domain into the cytosol of the target cells, allows them to be genetically engineered to replace their domains by other molecules of interest so as to direct them to new targets, when their B domain is replaced by other "ligands", or to deliver molecules into the target cells, when their A domain is replaced.

An AB toxin that is of particular interest to be used as a biotechnological tool is the AIP56. This toxin has tropism for macrophages and dendritic cells (DCs), which are the most important antigen presenting cells (APCs), and is capable of translocating molecules, distinct from its own catalytic domain, into the cytosol of these cells. Thus, by using molecular engineering techniques, the catalytic domain of AIP56 can be replaced by antigens expressed by cancer cells and delivered to the cytosol of APCs. Antigens delivered to the cytosol of APCs are processed and presented to T cells in the context of MHC I, inducing a cytotoxic immune response that is essential to fight cancer cells. In fact, therapies based on DCs stimulated ex vivo with tumor antigens and reintroduced into the patient have induced a cytotoxic response with tumor remission. Cytosolic expression of tumor antigens in DCs has also been shown to induce tumor rejection. However, despite the effort that has been made in developing techniques that allow the cytosolic administration of antigens, their success has been limited, making AIP56 and other toxins that have a B domain homologous to that of AIP56, giving them specificity for APCs, an added value to be used as vehicles for administering antigens into the cytosol of APCs and to enable the development of preventive and/or therapeutic vaccines against tumors. Therefore, the knowledge of the receptor to which the toxin binds and that defines toxin?s cellular specificity as well as the in-depth knowledge of the susceptible cell types allows not only to uncover essential aspects of the biology of the toxins with impact on the understanding of the pathology they cause, as to anticipate or even improve the immune response of patients who are to be vaccinated with these antigen delivery vehicles. This will be one of the aspects to be addressed in this project. In addition, mouse models will be used to carry out preliminary experiments to address the actual use of AIP56 as a tumor vaccination vehicle.

Galeria de fotos do projeto