Projektbeschreibung
Entschlüsselung der Endothelzellbiologie
Bestehende Therapien bei Herz-Kreislauf-Erkrankungen zielen oft darauf ab, durch die Abgabe vaskulärer Wachstumsfaktoren zu einer funktionellen Angiogenese anzuregen. Diese Methode zur Stimulierung einer Angiogenese gilt als besonders günstig, da sie die Proliferation und Sprossung von Endothelzellen fördert. Hoch mitogene Umgebungen führen jedoch auch zu einem signifikanten Zellzyklusarrest der Endothelzellen. Das EU-finanzierte Projekt AngioUnrestUHD wird mithilfe von fortschrittlichen genetischen Methoden und der Profilierung von Einzelzellen die Mechanismen hinter diesem Arrest entschlüsseln und modulieren. Das therapeutische Abzielen auf diese Mechanismen könnte ein effektiveres Induzieren der Angiogenese bei Herz-Kreislauf-Erkrankungen bzw. ihre effektivere Hemmung bei anderen Gefäßerkrankungen oder Krebs ermöglichen.
Ziel
Therapeutic modulation of vascular cell proliferation and migration is essential for the effective inhibition of angiogenesis in cancer or its induction in cardiovascular disease. The current view is that an increase in growth factor levels or mitogenic stimulation is beneficial for angiogenesis, since it leads to an increase in both endothelial proliferation and sprouting.
Through the use of innovative genetic and imaging approaches, we have recently elucidated a previously unappreciated, context-dependent mechanism whereby highly mitogenic environments can be detrimental for angiogenesis and lead to the cell-cycle arrest of endothelial cells (ECs), which ultimately impairs vascular growth.
The identified mechanism may explain the failed or inefficient promotion of functional angiogenesis by vascular growth factor delivery therapies, such as those used to treat ischemic cardiovascular disease. We propose that a better understanding and modulation of the identified hypermitogenic arrest process may allow angiogenesis to be induced more effectively.
Taking advantage of recent advances in DNA synthesis, CRISPR gene editing, microscopy and single-cell profiling technologies, we have developed new genetic tools, animal models and methods of broad relevance that enable the study of gene function with higher reliability, throughput and definition.
We propose to use these novel research tools and methods to significantly increase understanding of the biology of blood vessels in distinct physiological and pathological contexts.
We will then use this new knowledge to identify better strategies to promote vascular development in ischemic cardiovascular disease, heal vascular malformations, or inhibit angiogenesis in tumours.
Wissenschaftliches Gebiet
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- natural sciencesbiological sciencesgeneticsDNA
- natural sciencesphysical sciencesopticsmicroscopy
- medical and health sciencesclinical medicinecardiologycardiovascular diseases
- medical and health sciencesclinical medicineoncology
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
28029 Madrid
Spanien