Influence of Chronic Oral Infections on Senescence and Vascular Degeneration

• Applicants: Professorin Dr. Anette Melk, Ph.D.; Professorin Dr. Meike Stiesch
• Subject Area: Dentistry, Oral Surgery
• Term: from 2013 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 239928725

Chronic oral inflammatory diseases like periodontitis have been shown to be linked to adverse cardiovascular outcomes. The underlying mechanism of this correlation is largely unknown. Senescence refers to a phenotype of permanent irreversible growth arrest described in mammalian cells in culture, and several lines of evidence point towards an important role of senescence in aging processes in vivo. The fact that advanced age is associated with poor periodontal health and an increased prevalence and severity of periodontitis leads us to hypothesize (1) that periodontitis induce cellular senescence locally in gingival epithelial cells and via the systemically detectable microinflammation in endothelial cells. The later is the relevant link for the pathogenesis of endothelial dysfunction and eventually structural vascular changes, (2) that preexisting senescence will not only lead to a higher susceptibility towards local infections, but also to more periodontitis-induced changes in vascular function, and (3) that , as a proof of concept, interventional strategies interfering with senescence, like the specific knowdown of p16INKa in endothelial cells, will lead to protection from those periodontitis-induced changes by increasing the regenerative potential. We will study the induction of senescence by oral bacteria or bacterial-challenged cells in vitro using gingival epithelial and umbilical endothelial cells to. To further explore the direct impact of periodontitis-induced senescence for the induction of cardiovascular changes, i.e. the development of atherosclerosis, we will perform in vivo studies. For this purpose, experimental periodontitis will be induced in Apolipoprotein E knockout mice (ApoE KO mice) that spontaneously develop atherosclerotic plaques. P. gingivalis-treated ApoE KO mice will be compared with untreated controls to prove that periodontitis accelerates senescence and leads to greater cardiovascular changes. The comparison of young and old mice will clarify, whether preexisting senescence leads to higher susceptibility towards periodontitis-induced vascular changes. We will then use ApoE KO mice with a specific p16INKa knockdown in endothelial cells to test whether these mice are protected from the vascular changes seen in P. gingivalis-treated ApoE KO mice. These later studies will be the proof of concept that interfering with senescence leads to an increased regenerative potential that in turn helps to counteract the vascular changes caused by a chronic inflammatory process. Apart from its importance for the process of periodontitis, this project has further implications by providing evidence for a causal relationship between chronic inflammatory processes and vascular degeneration through the induction of senescent changes.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Jörg Eberhard