LICAMM Advanced glycation end products, diabetes and heart failure

Summary

Diabetes doubles the risk of developing heart failure. Recently, it has been shown that glycation of actin, which is increased in patients with diabetes, reduces calcium sensitivity [1,2]. Depressed calcium sensitivity is pathogenic for heart failure; therefore, myofilament glycation represents a promising therapeutic target to inhibit the development of heart failure in diabetics. To enable this, we need to understand myofilament glycation in more detail; which sarcomere proteins become glycated, what are the sites of glycation and modifications observed, and what is the effect of glycation on sarcomeric protein structure, interactions, and function? Different methylglyoxal modifications have been observed on myosin in diabetic patients compared to non-diabetics but the effects on myosin structure and interactions have not been explored. Glycation appears to lead to a reduced rate of attachment of myosin to actin, altering contraction. How glycation causes this is unknown but it may do this by stabilising an off-state of myosin termed the interacting-heads motif.

The aim of the project is to test the hypothesis that glycation of sarcomere proteins leads to dysregulation of contraction, contributing to the development of heart failure in diabetics. The objectives will be to:

• Determine the range of advanced glycation end products observed on key sarcomeric proteins by mass spectrometry (formed by treatment with different glycating agents e.g. methylglyoxal, glucose; comparing changes in expressed protein with those from skinned cardiomyocytes).
• Determine the effects of glycation on the structure, function and interactions of beta-cardiac myosin by biochemical assay, in vitro motility assay, electron microscopy and hydrogen-deuterium exchange mass spectrometry.

References

1. Papadaki, M. et al. Diabetes with heart failure increases methylglyoxal modifications in the sarcomere, which inhibit function. JCI Insight 3, (2018)
2. Papadaki, M. et al. Myofilament glycation in diabetes reduces contractility by inhibiting tropomyosin movement, is rescued by cMyBPC domains. J. Mol. Cell. Cardiol. 162, 1–9 (2022).

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject area is desirable but not essential.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.