Lei Group | Cardiac Signalling Group

+44 (01865) 271624
ming.lei@pharm.ox.ac.uk

Pioneering work on the roles of voltage-gated Na channels in cardiac pacemaking and sinus node dysfunction (J Physiol 2004, 2005, Circ Res 2010)

Determination of the cardiac protective roles of P21-activated kinases and therapy in heart disease conditions (Circ Res 2007, Circulation 2010, Circ A & E 2014)

Modernizing the classification of antiarrhythmic drugs (Circulation, 2018;138, 1879–1896)

Discovery of a novel population of catecholaminergic endocrine cardiomyocytes (Nature Comm 2023)

Our research mainly seeks to unravel the complexities of cardiac electrical function and its signalling regulation both in physiological and pathological conditions. It will lead to a better mechanistic understanding of hypertrophic and arrhythmic disorders, culminating in the development of more effective therapeutic interventions. We employ cutting-edge techniques encompassing genetic manipulation technologies and multi-scale electrophysiological, optogenetic, and molecular approaches.

Transmission electron microscopy (TEM) imaging: high electron density vesicles (arrowed) typical of catecholamine-containing chromaffin cells detected in cardiac myocytes

My group has made fundamental contributions towards identification of the novel roles of a multifunctional enzyme-p21 activated kinase (Pak1) in the heart. We demonstrated that Pak1 is central to the regulation of cardiac excitation and is a critical signalling hub in cardioprotection. We also have established Pak1 as a novel therapeutic target for treating cardiac disease conditions including cardiac arrhythmias.

We are now working on the future treatment of heart diseases using Pak1 as a novel target. Using structure-based rational drug design, we have already developed a series of novel Pak1 activator compounds as starting point compounds for the future drug development for the cardiac conditions.

We recently unveiled a remarkable previously unrecognised population of cardiomyocytes named "Dbh+ Catecholaminergic Cardiomyocytes" (Dbh+ Cate-CMs), paving the way for a potentially groundbreaking advancement in the field of neurocardiology. These cells, which express the enzyme dopamine-beta-hydroxylase (Dbh) and so can synthesise norepinephrine, originate from cardiomyocyte lineage, contribute to the development, maturation, and function of the cardiac conduction system (CCS). More importantly, the findings also suggest a close structural relationship between these cells and sympathetic innervation during the formation of the CCS. The physical co-localization of these cells, primarily within the ventricles, strongly implies a dynamic and vital interaction between Dbh+ Cate-CMs and the autonomic nervous innervation, which is already known to be highly abundant in the CCS.