Projektbeschreibung
Die Funktion der Mechanoradikale bei der Mechanoperzeption und Alterung von Kollagen
Seit langem ist bekannt, dass mechanischer Belastung ausgesetzte synthetische Polymere durch Bruch chemischer Bindungen Mechanoradikale erzeugen. Eigenschaften und biologische Relevanz von Mechanoradikalen in Proteinen sind unbekannt. Kollagen ist jedoch das Hauptstrukturprotein zahlreicher organischer Bindegewebe, deren Alterung in der Gesundheitsversorgung ein grundlegendes Problem darstellt. Das EU-finanzierte Projekt RADICOL wird die Funktion der Mechanoradikale bei der Alterung von biologischen Materialien in einem rechnerischen und experimentellen Ansatz untersuchen. Quantenchemische Berechnungen und Simulationen der Molekulardynamik werden die Bindungen und die nachfolgenden Radikalreaktionen in atomistischem Kollagen erkennen lassen. Diese rechnerischen Prognosen werden dann durch biochemische und biophysikalische Experimente überprüft. Das Projekt wird neue Erkenntnisse über die biologische Mechanoperzeption und Alterung erbringen.
Ziel
Our tissues, in particular collagen as the most abundant protein in our body, are constantly exposed to mechanical loads, reaching multiples of the body weight. In artificial polymers, mechanical loads are known for a century to cause radical formation and chemical degradation processes. Mechanoradicals from bond ruptures, being highly reactive and oxidising, deteriorate the material, leading to stiffening and ageing. Ageing of organic tissue is a fundamental problem in health and disease, but a role of mechanoradicals has been a blind spot. Our simple but novel idea is to test the role of mechanoradicals for ageing of biomaterials. As a starting point, we have recently uncovered mechanoradicals in tensed tendon collagen. They readily react with water to form reactive oxygen species (ROS), key signalling molecules in a multitude of physiological processes including ageing.
I hypothesise that mechanoradicals generate a feedback loop resulting in accelerated collagen ageing. Using a scale-bridging combined computational and experimental approach, I will dissect the full lifecycle of mechanoradicals in collagen, from bond scission and radical migration to ROS formation, to uncover new mechanisms of radical-mediated ageing. We will perform quantum chemical calculations and Molecular Dynamics (MD) simulations, including a new reactive Monte Carlo/MD scheme, to identify scissile bonds and subsequent radical reactions in atomistic collagen I fibril models. For validation, a combination of electron-paramagnetic resonance spectroscopy, mass spectrometry and other biophysical experiments will be employed to measure degradation pathways, radicals and ROS under varying crosslink densities and types as present in young, aged and diseased tendon tissues.
RADICOL will establish protein mechanoradicals as an as yet uncovered source of oxidative stress, and as a new paradigm of biological mechanosensation and ageing.
Wissenschaftliches Gebiet
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
69117 Heidelberg
Deutschland