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Angiogenesis in zebrafish: how are vascular networks formed?

English title Angiogenesis in zebrafish: how are vascular networks formed?
Applicant Affolter Markus
Number 200701
Funding scheme Project funding (Div. I-III)
Research institution Abteilung Zellbiologie Biozentrum Universität Basel
Institution of higher education University of Basel - BS
Main discipline Embryology, Developmental Biology
Start/End 01.04.2021 - 31.03.2025
Approved amount 997'246.00
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Keywords (3)

angiogenesis; zebrafish; development

Lay Summary (German)

Lead
Wie werden Blutgefässnetzwerke aufgebaut?
Lay summary

Blutgefässe sind unerlässlich für die Entwicklung und das Leben von Wirbeltieren. Ausgehend vom Herzen wird das Blut und alle seine essentiellen Bestandteile in immer feiner werdendes Verästerungen zu allen Organen geführt, wo in unzähligen Haargefässen oder Kapillaren der Sauerstoffaustausch zwischen Blut und Geweben stattfindet. Danach vereinigen sich die Kapillaren wieder zu grösseren Röhren, die wieder zum Herz zurückführen. Wie dieses komplexe Netzwerk von Gefässen mit all seinen architektonischen Besonderheiten während der Entwicklung aufgebaut ist, ist noch nicht im Detail erforscht, vor allem auch deshalb, weil Blutgefässbildung nicht in einfacheren Lebewesen erforscht werden kann (da diese gar kein solches Netzwerk haben), und weil die Betrachtung der Entwicklung des Blutgefässsystems in der Embryonalentwicklung der Maus nicht möglich ist, weil sich der Embryo in der Gebärmutter entwickelt.

In den letzten Jahren wurde deshalb die Blutgefässbildung in Zebrafischembryonen untersucht, die sich ausserhalb des Muttertieres im Wasser entwickeln und durchsichtig sind, was die Betrachtung und Dokumentation der Entwicklungsschritte vereinfacht. Wir haben wichtige Beiträge zur Beschreibung und der Analyse der verschiedenen Zellaktivitäten, die der frühen Blutgefässbildung unterliegen, geliefert. In den nächsten vier Jahren möchten wir untersuchen, wie die organ-spezifische Blutgefässnetzwerke aufgebaut werden. Diese Arbeiten sollten ein umfassendes Bild geben, wie komplexe, diversifizierte Blutkreisläufe aufgebaut werden und schlussendlich funktionieren. Da Blutgefässe eine so wichtige Funktion in allen Organen übernehmen, ist zu erwarten, dass diese Studien einen Einfluss auf viele andere Forschungsgebiete haben werden, von der Grundlagenforschung hin bis zu klinischen Studien.

 

Direct link to Lay Summary Last update: 30.03.2021

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
176400 In vivo cell biology of organ morphogenesis 01.12.2017 Project funding (Div. I-III)
192659 Drosophila Branching 2.0 01.04.2020 Project funding (Div. I-III)

Abstract

Summary of the Research Plan (put together with the help of Heinz-Georg Belting and Maria Kotini, a scientific collaborator and a postdoc in the lab, respectively)Blood vessels are dynamic structures that provide tissues with oxygen and nutrients, endocrine signals and immune access. Understanding how blood vessels grow, mature and remodel is fundamental to many fields of medicine, including would healing, cancer therapy, and tissue engineering. Early studies in mice have relied heavily on genetic and lineage tracing studies and have uncovered a wealth of information about how the vasculature forms and how this is controlled at the molecular level. In more recent years, research has turned its focus on endothelial cell (EC) behaviours which drive vascular network formation and remodelling, and made efforts to include cell dynamics in the analyses. However, at present, it is still difficult or close to impossible to visualize specific cell behaviours over time in mammals. Over the last years, the zebrafish have emerged as a unique system to study EC biology in vivo. Zebrafish embryos develop outside the mother as the egg is laid into the water, the embryos are transparent and many transgenic lines expressing fluorescently tagged proteins in different tissues and cell compartments have been generated. Live imaging of the developmental vasculature has provided insight into cell behaviour during vasculogenesis, angiogenesis (including sprouting, anastomosis, and lumen formation) and in vascular remodelling (including vessel pruning). These studies have also allowed to link molecular players identified in mammalian systems or in cultured cells to EC behaviour in zebrafish through genetic and reverse genetic approaches.One of the striking observations made using live imaging is the high degree and the pivotal role of EC rearrangements during sprouting, anastomosis and during vessel remodelling. We have recently described so-called Junction-Based Lamellipodia (JBL), which accompany and possibly steer these cell rearrangements in sprouting and in anastomosis. We want to better understand the molecular control of the oscillatory behaviour of JBLs and study their importance in cell rearrangements underlying distinct aspects of vascular remodelling.Much of the vascular network of a given organism is made up by the microvasculature, which consists of arterioles, linked via fine capillaries to venules. The microvasculature is to a large extent responsible for the exchange of oxygen and waste with target tissues and has to reach within some 100 ?m to all cells of the body. Despite its tremendous functional importance, the formation and maturation of microvasculature networks have not been studied much in vivo at the cellular level. We want to capitalize on our live imaging expertise and study microvascular development in different organs at the cellular and molecular level in the zebrafish. Furthermore, we want to extend our pioneering studies on vessel pruning, since we expect pruning to be an integral process in microvasculature development and maturation.We would like to answer the following questions:1)How do ECs rearrange during angiogenesis processes?2)How does the microvasculature form and mature?For our studies, we thus propose the following the three aims:1)Characterize the molecular control of cell rearrangements in angiogenesis2)Study the architecture and formation of organ-specific microvasculature3)Study the cellular and molecular control of vascular pruning In order to answer these questions, we propose to apply the following experimental strategies:1)Capitalize and expand on our live imaging expertise2)Generate additional transgenic lines, many with photoconvertible FPs3)Reverse genetic analyses of candidate genes using Crispr-Cas9
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