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Mechanisms of MTOC guidance and Genetic Transfer at the Immune Synapse: novel modes of Immuno-modulation

Objective

"Cell-cell synapses are an exquisitely evolved means of communication between cells. During the formation of the immune synapse (IS), diverse transmembrane and membrane associated molecules are reorganized into a highly segregated structure at the T cell–Antigen-Presenting Cell (APC) contact site. As part of this process, the tubulin cytoskeleton is vectorially directed toward the center of the IS, where the microtubule-organizing center (MTOC) localizes. MTOC translocation is an early event in IS formation that brings the secretory apparatus into close apposition with the APC, thus providing the basis for polarized secretion.

The proposal aims to define how the MTOC controls cytoskeletal rearrangement and communication at the IS, as a mechanism for macromolecule transport and nucleation of signalling molecules during synaptic contact. We will study the mechanisms of MTOC-mediated polarization of multivesicular bodies (MVB) and exosome delivery during IS formation, and will assess the role in these processes of MTOC translocation regulators (HDAC6) and microtubule (MT) polymerization promoters (Plk1 and EB1). MTOC-dependent mitochondrial polarization to the IS will be assessed as a bioenergetic source for cytoskeletal rearrangements, IS maturation and polarized exosomal delivery. In particular, our proposed study of the possible horizontal transfer of miRNAs during cognate interactions between immune cells has the potential to reveal how miRNAs can control the early initiation of immunity. We will investigate the mechanism of directional transfer of RNA-harbouring exosomes at the IS from T cell to APC, and will examine the functional consequences of this transfer on APC biology and on the immune response. These studies will open avenues for the treatment of immune-related diseases."

Field of science

  • /medical and health sciences/health sciences/public and environmental health/epidemics prevention/immunisation

Call for proposal

ERC-2011-ADG_20110310
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Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III (F.S.P.)
Address
Calle Melchor Fernandez Almagro 3
28029 Madrid
Spain
Activity type
Research Organisations
EU contribution
€ 1 512 000
Principal investigator
Francisco Sánchez Madrid (Prof.)
Administrative Contact
Luzma García Piqueres (Ms.)

Beneficiaries (2)

CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III (F.S.P.)
Spain
EU contribution
€ 1 512 000
Address
Calle Melchor Fernandez Almagro 3
28029 Madrid
Activity type
Research Organisations
Principal investigator
Francisco Sánchez Madrid (Prof.)
Administrative Contact
Luzma García Piqueres (Ms.)
UNIVERSIDAD AUTONOMA DE MADRID
Spain
EU contribution
€ 499 200
Address
Calle Einstein 3 Ciudad Univ Cantoblanco Rectorado
28049 Madrid
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Mª Carmen Puerta (Ms.)