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Synthetic Cell Biology: Designing organelle transport mechanisms

Descripción del proyecto

Diseño de vesículas sintéticas en células vivas

Las células contienen una compleja red de orgánulos y vesículas delimitados por una membranas que participan en la síntesis, procesamiento y transporte de macromoléculas, como proteínas y lípidos, destinados a la secreción o a su uso dentro de la célula. Esta red desempeña un papel crucial en diversos procesos celulares, como la secreción de hormonas y el mantenimiento de la homeostasis celular. El equipo del proyecto ArtifiCell, financiado por el Consejo Europeo de Investigación, se centra en el concepto de diseñar nuevos mecanismos de transporte de vesículas en células vivas. Los investigadores se proponen diseñar la maquinaria proteínica básica implicada en la formación, focalización y fusión de vesículas. Para ello, introducirán vesículas sintéticas a base de fosfolípidos y ácidos péptido-nucleicos para redirigir las vesículas secretoras hacia dianas específicas.

Objetivo

Imagine being able to design into living cells and organisms de novo vesicle transport mechanisms that do not naturally exist? At one level this is a wild-eyed notion of synthetic biology.
But we contend that this vision can be approached even today, focusing first on the process of exocytosis, a fundamental process that impacts almost every area of physiology. Enough has now been learned about the natural core machinery (as recognized by the award of the 2013 Nobel Prize in Physiology or Medicine to the PI and others) to take highly innovative physics/engineering- and DNA-based approaches to design synthetic versions of the secretory apparatus that could someday open new avenues in genetic medicine.
The central idea is to introduce DNA-based functional equivalents of the core protein machinery that naturally form (coats), target (tethers), and fuse (SNAREs) vesicles. We have already taken first steps by using DNA origami-based templates to produce synthetic phospholipid vesicles and complementary DNA-based tethers to specifically capture these DNA-templated vesicles on targeted bilayers. Others have linked DNA oligonucleotides to trigger vesicle fusion.
The next and much more challenging step is to introduce such processes into living cells. We hope to break this barrier, and in the process start a new field of research into “synthetic exocytosis”, by introducing Peptide-Nucleic Acids (PNAs) of tethers and SNAREs to re-direct naturally-produced secretory vesicles to artificially-programmed targets and provide artificially-programmed regulation. PNAs are chosen mainly because they lack the negatively charged phosphate backbones of DNA, and therefore are more readily delivered into the cell across the plasma membrane. Future steps, would include producing the transport vesicles synthetically within the cell by externally supplied origami-based PNA or similar cages, and - much more speculatively - ultimately using encoded DNA and RNAs to provide these functions.

Régimen de financiación

ERC-ADG - Advanced Grant

Institución de acogida

UNIVERSITY COLLEGE LONDON
Aportación neta de la UEn
€ 2 200 000,00
Dirección
GOWER STREET
WC1E 6BT London
Reino Unido

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Región
London Inner London — West Camden and City of London
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
€ 2 200 000,00

Beneficiarios (2)