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Real time Exploration of GTPase-Cytoskeletal feedback underlying Contractile Actomyosin Systems

Applicant Pertz Olivier
Number 183550
Funding scheme Sinergia
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Berne - BE
Main discipline Interdisciplinary
Start/End 01.09.2019 - 31.08.2023
Approved amount 2'188'972.00
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All Disciplines (3)

Discipline
Interdisciplinary
Cellular Biology, Cytology
Other disciplines of Physics

Keywords (7)

mathematical modelling; live cell imaging; FRET biosensors; Rho GTPases; cell/tissue morphogenesis; modelling; cytoskeletal dynamics

Lay Summary (French)

Lead
Exploration de boucles de rétroaction entre le cytosquelette et la signalisation de GTPase Rho dans des systèmes de contractilité base sur la myosineLes processus de motilité cellulaire, de cytokinese, et de morphogenèse sont régulée d’une manière extrêmement précise qui fonctionnent à des échelles spatiales de l’ordre du micron, et des échelles temporelles de l’ordre de la seconde. Les outils de biologie moléculaire et cellulaire ne permettent en ce moment pas de comprendre ces processus extrêmement dynamiques. Le but de ce projet et de construire de nouveaux outils qui permettent d’analyser ces mécanismes de régulation extrêmement sophistiqués, qui fonctionnent à ces échelles spatio-temporelles.
Lay summary

Contenu et objectifs du travail de recherche.

 

Le but de ce projet est de mettre en œuvre de nouveaux outils pour étudier la signalisation cellulaire qui régulent le cytosquelette, et les boucles de rétroaction du cytosquelette a la signalisation qui permettent la régulation fine dans le temps et l’espace de processus comme la motilité cellulaire, la cytokinese et la morphogenèse cellulaire. Nous utiliserons des biosenseurs, et des marqueurs du cytosquelette pour visualiser la régulation spatio-temporelle de ces processus. Pour perturber ces systèmes cellulaires, nous utiliserons des outils optogénétique pour contrôler le cytosquelette et la signalisation avec une résolution de l’ordre du micron et de la seconde. Nos données seront ensuite utilisées pour produire des modèles mathématiques de ces processus cellulaire avec un nouveau degré de résolution.

 

Contexte scientifique et social du projet de recherche

 

Notre approche multidisciplinaire a le potentiel de donner des nouvelles idées pour contrôler des processus patho-physiologique comme le cancer, la progression métastatique ou l’inflammation.

Direct link to Lay Summary Last update: 29.03.2019

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
136061 Le travail sociologique et la sociologie du travail : rencontres avec Howard S. Becker 01.10.2011 Scientific Conferences
185376 Decoding and Re-Encoding Receptor Tyrosine Kinase/Fate Decision Signaling 01.06.2019 Project funding (Div. I-III)
198524 Cryo-focused ion beam scanning electron microscope to prepare cells for visualising their molecular architecture by electron cryo-tomography 01.11.2021 R'EQUIP
189781 A photo-manipulation unit for high precision, 3-dimensional photoactivation and laser ablation on a multi-view light sheet microscope setup 01.12.2019 R'EQUIP
175996 Theoretical study of active gel dynamics in evolving domains using phase fields 01.12.2017 Project funding (Div. I-III)

Abstract

Cytoskeletal networks are master regulators of cell shape and drive numerous processes such as cell division, cell migration, or wound healing. The collective dynamics of the relevant proteins - filaments, motors, and crosslinkers - can be quantitatively described with predictive power through active gel theory. In addition to their self-organizing properties, which have been extensively studied, cytoskeletal networks in living cells display architectural and dynamic features, which critically depend on spatial and temporal cues from signaling proteins that provide cell type- and cell cycle-specificity. These comprise particularly enzymes known as GTPases that can bind and hydrolyze the nucleotide guanosine triphosphate. In contrast to the prevailing view that the three canonical GTPases RhoA, Rac1, and Cdc42 independently regulate certain cellular functions such as contractility and lamellipodia or filopodia formation, recent data indicate that different GTPases cooperate to form specific spatio-temporal signaling patterns. These interactions involve proteins that regulate GTPase activity called guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Another emerging theme is that feedback mechanisms from cytoskeletal components to Rho GTPases are necessary to shape Rho GTPase signaling patterns on time scales of seconds and length scales of micrometers. Consequently, cytoskeletal structures with the ability to self-organize form an integral part of the spatially-organizing Rho GTPase signaling network, a unit we call a “morphoregulon”. The interplay between active gels and the systems biology of signaling networks is currently poorly characterized. This is mainly due to the difficulties in measuring and manipulating with the current technological toolkits cellular signaling processes at the relevant time and length scales of seconds and micrometers, respectively. Here, we propose to use innovative tools from optogenetics, chemical biology, and single cell live imaging merged with theoretical analysis, to study the dynamics of morphoregulons. In this vein, we have recently developed prototype methods that allow sub-cellularly measuring and perturbing GTPase-mediated signaling and cytoskeletal dynamics at relevant spatio-temporal scales. We plan to continue this development and to apply the novel tools to a variety of experimental systems with complementary features: O. Pertz will study the morphoregulon controlling the highly dynamic leading edge of migrating fibroblasts, D. Brunner that of the periodically contracting cells driving tissue morphogenesis, as well as that controlling cell wound healing, and D. Riveline will study the morphoregulon controlling contractile cytokinetic actomyosin rings and supra-cellular actomyosin rings that cells form around a tissue opening. Our groups will collaborate to design and implement genetic circuits consisting of spectrally compatible optogenetic and chemical biological actuators, which can be simultaneously used with biosensors that report on spatio-temporal Rho GTPase activation. Finally, K. Kruse will extend active gel theory to account for the effects of signaling, physically characterize and comprehensively classify possible morphoregulons, and use the data by the experimental partners to apply his general framework to the specific morphoregulons they study. Through our joint efforts that merge state of the art technologies for quantifying and perturbing signaling networks and cytoskeletal dynamics in individual cells of different model systems with theory, we expect to identify the underlying logic of prototype morphoregulons and to identify novel states of living matter.
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