Apoptosis and senescene in the contol of mitral valve interstitial cell persistence

Myxomatous mitral valve disease (MMVD) is an important valvulopathy of both the dog and human (Barlow’s Disease) that can result in heart failure. The disease in both species is caused by aberrant extracellular matrix (ECM) remodelling as a consequence of activation of valve interstitial cells (aVICs). The ubiquity of the disease in the dog and the ready availability of both normal and diseased canine valves makes the dog an excellent natural model for Barlow’s Disease. While the exact cause of MMVD is unknown, TGFβ signalling is crucial to disease development and aVICs can be transitioned to a normal phenotype by antagonising TGFβ canonical and non-canonical signalling pathways. Overall, TGFβ signaling is complex such that it can have a wide range of diverse effects on target cells, including control of cell apoptosis (programmed cell death) and cell senescence (cells stop dividing).
We have identified persistence of aVICs in diseased valves suggesting increased resistance to cell apoptosis or heightened cell senescence. A range of genes associated with apoptosis and senescence, including BCL family members, CASP8, DED, DAD1, the angiopoetins and pleotrophins, and the genes encoding P21 and P16, are up-regulated in diseased valves, and cultured normal and diseased VICs show differences in their apoptotic state and associated gene expression. The hypothesis for this study is that altered VIC apoptosis and/or senescence contribute to VIC persistence, and thereby to the progressive aberrant remodelling typical of MMVD. This project will characterise the apoptotic/senescent state of VICs in 2D and 3D cell culture methods (under static and mechanical strain conditions), using a combination of RT-PCR, protein immunoblotting, immunocytochemistry, ELISAs for collagens and proteoglycans (synthetic activity), pharmacological manipulation and mRNA interference technologies. The specific aims are to confirm the apoptotic/senescent state of aVICs and to demonstrate that these states can be manipulated thereby identifying novel therapeutic targets for disease control applicable to both the dog and human.

Other projects available:
We would encourage applicants to list up to three projects of interest (ranked 1st, 2nd and 3rd choice) from those listed with a closing date of 10th January 2020 at https://www.ed.ac.uk/roslin/work-study/opportunities/studentships