Project

Back to overview

Molecular dynamics in hematopoietic stem and progenitor cell fate control

English title Molecular dynamics in hematopoietic stem and progenitor cell fate control
Applicant Schroeder Timm
Number 179490
Funding scheme Project funding (Div. I-III)
Research institution Computational Systems Biology Department of Biosystems, D-BSSE ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Cellular Biology, Cytology
Start/End 01.06.2018 - 31.05.2022
Approved amount 1'112'000.00
Show all

All Disciplines (2)

Discipline
Cellular Biology, Cytology
Molecular Biology

Keywords (10)

Microfluidics; Imaging; Dynamics; Computational modeling; Signaling; Networks; Stem cell; Transgenic mouse; Transcription factor; Cell fate

Lay Summary (German)

Lead
Netzwerke von Molekülen wie Transkriptionsfaktoren und Komponenten von Signalübertragungswegen steuern das Verhalten aller Zellen des Blutsystems. Ihre eigene Regulation und Dynamiken sind bisher jedoch schlecht verstanden. Das Projekt quantifiziert die Dynamiken dieser Moleküle in Stamm- und Vorläuferzellen des Blutsystems kontinuierlich über lange Zeiträume auf Einzelzellebene.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Unser Blutsystem produziert jede Sekunde des Lebens Millionen neue Blutzellen. Signalübertragungswege und Transkriptionsfaktoren steuern das Verhalten aller Zellen des Blutsystems. Wie diese Moleküle, welche zu Netzwerken zusammengeschaltet sind, in einzelnen Zellen reguliert sind ist jedoch schlecht verstanden. Insbesondere gibt es bislang wenige Daten zu ihrer dynamischen Expression oder Aktivität in individuellen Zellen.

Das Projekt verwendet eine Kombination aus neuartigen Mikroskopieverfahren, molekularbiologischen Methoden, Softwareentwicklung und Ingenieursmethoden um die Dynamiken verschiedener Moleküle in einzelnen lebenden Blutzellen zu quantifizieren. Diese Daten werden es erlauben besser zu verstehen wie diese Moleküle zu Netzwerken zusammengeschaltet sind, wie diese Netzwerke reguliert sind, und wie dies die Differenzierung einzelner Blutstamm- und Vorläuferzellen kontrolliert.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Das Projekt befasst sich mit Grundlagenforschung. Das Ziel ist eine Quantifizierung der Dynamik von Transkriptionsfaktoren und Signalübertragungsmolekülen in Blutzellen. Dies ist notwendig um die molekulare Steuerung des gesunden Blutsystems, und die Ursachen hämatologischer Erkrankungen wie z.B. Leukämien, besser verstehen und klinisch beeinflussen zu können.

Direct link to Lay Summary Last update: 24.05.2018

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
156431 Transcription factor dynamics in hematopoietic cell fate control 01.06.2015 Project funding (Div. I-III)
189807 Multiphoton Confocal Microscope for High-Speed and High-Resolution Imaging 01.09.2020 R'EQUIP
156431 Transcription factor dynamics in hematopoietic cell fate control 01.06.2015 Project funding (Div. I-III)

Abstract

Despite the importance of hematopoietic stem and progenitor cells (HSPCs), their molecular control remains poorly understood. Transcription factors (TFs) and their networks (TFNs) play a central role in controlling HSPC fates. However, it is unclear how the TF expression in their TFNs is regulated. Extracellular signals, transmitted through intracellular signaling pathways are central regulators of HSPC TFNs and fates. It is becoming increasingly clear that not only the combinatorial activity of signaling pathways, but the dynamics of signaling pathway activity is crucial for their effects on molecular targets and thus cellular decision making. However, signaling dynamics are typically ignored in current research, in particular when working with primary adult mammalian stem and progenitor cells. One major reason is that complex HSPC differentiation systems are usually analyzed at only the population level and / or only at individual time points. However, for a comprehensive understanding of molecular dynamics and cell fate control, both cell behavior and molecular expression or activity must be quantified at the single cell level and continuously over many days. We therefore develop novel bioimaging systems allowing the continuous long-term quantification of cell behavior and protein expression or activity in individual differentiating cells. We will use these approaches to quantify, continuously and at the single cell level, cellular behavior, TF expression and cytokine signaling pathway activity during HSPC differentiation. In combination with novel reporter mouse lines for reporting signaling activity, this novel kind of data will be used to generate improved understanding of TFN regulation and HSPC fate control. Microfluidic devices will be optimized to allow the high throughput combinatorial and dynamic manipulation of culture conditions during long term time-lapse of human and mouse HSPC cultures. We expect much improved insights into the regulation and role of signaling pathways and TFN regulation in controlling clinically relevant mammalian HSPC fates.
-