Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. (360G-Wellcome-106562_Z_14_Z)
Recent collaborative work demonstrated that mitochondrial DNA (mtDNA) damage and mitochondrial dysfunction occur early in atherosclerosis and that they are linked to vascular smooth muscle cell (VSMC) senescence and cell death as well as pro-inflammatory signalling through monocytes. Importantly, mitochondrial DNA damage is also correlated with atherosclerosis and features of plaque vulnerability in humans (Yu et al Circulation 2013). However, the mechanisms by which mitochondrial DNA damage and dysfunction are linked to early atherosclerosis are currently not elucidated. While some of these effects are likely mediated through reactive oxygen species (ROS), many are not. In particular, although many genes associated with inflammation are redox-regulated, mitochondrial DNA that has been damaged can also act as a damage associated moleculal pattern (DAMP) further perpetuating inflammation in part via the NLRP3 inflammasome and/or toll­ like receptors. Interestingly recent studies have suggested that inflammation can induce a metabolic shift in cells from oxidative phosphorylation to glycolysis. This so called Warburg effect is observed in cancer cells but more recently was also linked to activation of inflammatory cells.This application will investigate the link between mitochondrial dysfunction, metabolism and inflammation in the early stages of atherosclerosis: 1. Identify the time course of mtDNA damage/dysfunction and determine how mitochondrial metabolism alters in early atherosclerosis. 2. Identify redox-regulated proteins that are altered in early atherosclerosis and after exposure of smooth muscle cells to known mediators of atherosclerosis and inflammation. 3. Determine whether improvement of mitochondrial function by increasing mtDNA copy number prevents atherosclerosis.
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Grant Details
Amount Awarded | 224569 |
Applicant Surname | Reinhold |
Approval Committee | PhD Studentships |
Award Date | 2014-09-15T00:00:00+00:00 |
Financial Year | 2013/14 |
Grant Programme: Title | PhD Training Fellowship for Clinicians |
Internal ID | 106562/Z/14/Z |
Lead Applicant | Dr Johannes Reinhold |
Partnership Value | 224569 |
Planned Dates: End Date | 2017-09-30T00:00:00+00:00 |
Planned Dates: Start Date | 2014-08-06T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | East of England |
Sponsor(s) | Prof Krishna Chatterjee |