Prof. Dr. Christian Weber, MD, Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University
Personal web site address: http://ipek.klinikum.uni-muenchen.de/
E-mail address: firstname.lastname@example.org
Research interests abstract
Vascular disease including coronary artery disease (CAD) and stroke is the leading cause of death and morbidity worldwide and imposes exorbitant socioeconomic costs. This dilemma could be limited by improving vascular prevention and therapy based on a refined mechanistic pervasion of atherosclerosis as the underlying pathology, prompting a more efficient and reliable identification of new targets for subsequent translation. The latter is mandated by the stagnating success rates in the clinical trial phase, which illustrate inherent pitfalls of cardiovascular drug development.
The mission of our institute and my working will be to improve the identification and validation of new strategies for treating atherogenesis, atheroprogression and atherothrombosis in a pathological sequence of CAD. Atherogenesis is driven by a disturbed equilibrium of lipid accumulation, maladaptive immune responses and their clearance, entailing chronic inflammation of the artery wall, crosstalk with pro-coagulant pathways and culminating in plaque rupture and thrombosis. New atherogenic and protective pathways mutually linking lipids, inflammation and coagulation biology have been discovered, and profiling studies have unveiled risk genetic variants as well as epigenetic factors for CAD, giving rise to complex network effects (Weber & Noels Nat Med 2011;17:1410-22).
Recent examples include the complex functional and biochemical interactions in the chemokine interactome driving atherogenic mobilization and recruitment of monocytes (Koenen et al. Nat Med 2009;15:97-103; Soehnlein et al. EMBO Mol Med 2013; 5:471-81) or suppressing regulatory T-cell maintenance (Weber et al. J Clin Invest 2011; 121:2898-910), the relevance of the CXCL12/CXCR4 chemokine-receptor axis supported by the miRNA-126 in controlling neutrophil homeostasis and promoting endothelial repair to protect from atherosclerosis (Zernecke et al. Circ Res 2008;102:209-17 Sci Signal 2:ra81) or the endothelial-specific role of junctional adhesion molecule-A in guiding monocytes into flow-dependent predilection sites of atherosclerosis (Schmitt et al. Circulation 2013; ePub).
Bioinformatic network analysis will be instrumental for developing biopharmaceuticals for CAD, which may outperform classical drug candidate and high-throughput approaches, as structure-function relationships can be readily probed, while off-target effects and toxicity can be better predicted. The identification of worthwhile targets within such networks requires unbiased screening of different families, a thorough pathogenetic basis and analysis of their interactions in relevant model systems.
We aim to systematically elaborate intricately linked molecular mechanisms of different target families - cytokines, signal proteins, nucleotides and lipid mediators - allowing for a sufficiently broad yet coherent spectrum. We propagate their validation by molecular imaging technologies in animal models or human tissue.