RhoSNATCH · Dissecting Rho GTPase signalling networks through acute perturbation techniques
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2017-04-01 → 2019-03-31
- Финансиране от ЕС
- 187 420 €
- Участници
- 1
- Схема
- MSCA-IF-EF-ST
Линиите свързват координатора с партньорите.
Накратко на български
Молекулярните механизми, които управляват движението на клетките, се анализират чрез нови методи за редактиране на генома и микроскопия. Разбирането на тези процеси помага при търсенето на нови мишени за лечение на метастазите при рака.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Dissecting Rho GTPase signalling networks through acute perturbation techniques
Cancer is the second leading cause of death in the world, with 9 million reported deaths annually. Metastatic cancer, where secondary tumors are spread from the primary tumor into the rest of the body, still accounts for the majority of cancer-related deaths. Metastatic cancer starts with the cell migration of tumor cells from the primary tumor into the bloodstream. From the bloodstream cancer cells can extravasate to form metastatic tumors elsewhere in the body. Understanding the machinery that governs the migration and extravasation of the cells in metastatic cancer is critical for the development of new therapies to fight this deadly disease that plagues humanity. The project RhoSNATCH aims to further our understanding of the processes underlying cell movement in healthy and diseased cells on a molecular level. RhoSNATCH aims to identify the critical molecular players in the signaling network that underlies cell motility. Cellular motility is very strictly organized on timescales of seconds and with micrometer precision to allow for highly controlled behavior in the different tissues of the human body. The machinery that controls this cellular motility is very sensitive to perturbation from outside the cell (mechanical or chemical), which leads to adaptation of the cellular structures that govern cellular motility. Because of this reason it is difficult to study this subject, as classical experimental methods all strongly perturb the cellular structures under study. By combining state of the art genome editing and advanced fluorescent microscopy techniques RhoSNATCH can now address questions about cell migration that were inaccessible before. By answering these novel questions RhoSNATCH contributes to the search for new molecular targets in the treatment for metastatic cancer. We identified the effects of the acute perturbation of one of the major drivers in cell migration and are currently exploring the effects of several other proteins involved in cell motility.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Recent advances in technologies to measure Rho GTPase signaling with unprecedented spatiotemporal resolution in single living cells have led to novel questions. Important new insights are that Rho GTPase signaling involves the formation of signaling complexes that fluctuate on subminute time and micrometer length scales, and that complex signaling networks involving multiple Rho GTPases fine tune the leading edge dynamics that power fibroblast migration. Novel methodologies are required to dissect this newly discovered signaling complexity. RhoSNATCH aims to characterize these signaling networks by acutely perturbing and recording Rho GTPase signaling at biologically relevant timescales in live-cell imaging experiments of cell migration. I will identify the crosstalk between Rac1/RhoA/Cdc42 that positions and maintains specific Rho GTPase activity zones in time and space and identify dedicated functional signaling modules that fine tune specific cytoskeletal output at the leading edge of motile fibroblasts. Microfluidic technology will be used to induce precise fibroblast leading edge signaling states. Genome editing in combination with a reversible chemical dimerizing system will be used to acutely perturb endogenous RhoA,Cdc42 and Rac1 signaling, as well as a subset of their upstream regulators that regulate leading edge dynamics. Rho GTPase activation patterns and downstream cytoskeletal outputs will be systematically recorded in the different perturbed states. Computer-vision assisted image analysis will allow the multiplexing of multiple data sets to produce one of the first integrated models of the molecular circuitry that fine-tunes Rho GTPase signaling and cytoskeletal dynamics during leading edge extension. This novel, integrated approach will allow for the first time the identification of different spatiotemporally organised Rho GTPase signaling modules, and give relevant insight into the crosstalk between and functions of Rho GTPases in time and space.
Оригинален текст от CORDIS (на английски).
Участници
- UNIVERSITAET BERN · BernКоординаторШвейцария
Връзки
Данни: CORDIS, © Европейски съюз