Project Details
Projekt
Epigenetic regulation of smooth muscle cell plasticity in human vascular disease
Applicant
Privatdozent Dr. Till Althoff
Subject Area
Cardiology, Angiology
Term
from 2014 to 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 259313274
Unlike skeletal or cardiac muscle cells, which are terminally differentiated, vascular smooth muscle cells are highly plastic. This ability to dedifferentiate and redifferentiate is a prerequisite for vascular remodeling processes that physiologically enable vascular development and repair, as well as adaptation to altered hemodynamics. However, smooth muscle cell plasticity also plays a key role in the pathogenesis of vascular diseases. The differentiation state of smooth muscle cells is reflected by the expression of smooth muscle differentiation marker genes, the majority of which are under control of the transcription factor serum response factor. We could recently demonstrate that G12/13- and Gq/11-mediated signaling pathways regulate smooth muscle differentiation antagonistically by controlling the recruitment of transcriptional co-factors of the myocardin family and the ternary complex factor family, respectively, by serum response factor. However, these mechanisms do not sufficiently explain the smooth muscle specific expression patterns in vivo. Accumulating evidence suggests that smooth muscle cell plasticity is co-regulated by epigenetic mechanisms in terms of chromatin modifications. However, it is scarcely defined by which chromatin modifying enzymes and upstream signaling pathways these modifications are established and regulated. Moreover, the underlying data is almost exclusively based on cell culture experiments, and it remains to be determined, wether these epigenetic mechanisms are of significant relevance in vivo and particularly in human vascular diseases. The goal of this project is to close these gaps and to investigate epigenetic mechanisms that control smooth muscle cell plasticity in the context of atherosclerosis and aneurysmal disease. Besides applying murine disease models we will perform a patient study to acquire and analyse human vascular samples. Of particular interest will be the role of dysregulated chromatin modifying enzymes as potential pharmacological targets. Focusing on G-protein mediated signaling we further aim to characterise upstream regulatory pathways. The ultimate goal is to translate the findings through to the validation of pharmacological agents in vivo. In light of the dramatic impact of smooth muscle specific G-protein deficiencies, not only on smooth muscle cell plasticity, but in particular on the progression and mortality of vascular diseases in animal models, pharmacological modulation of smooth muscle cell plasticity appears to be a promising therapeutic concept. In this regard chromatin modifying enzymes are generally considered well targetable by pharmacological agents.
DFG Programme
Research Grants
