More than 1000 mutations in sarcomere protein genes have been identified to cause familial hypertrophic cardiomyopathy (HCM), the most common inherited disease. Recent metabolic and energetic studies highlight the importance of the intracellular homeostasis of cardiomyocytes in HCM. The pathogenesis, however, from a single mutation to comprehensive and often heterogeneous cardiac tissue remodelling, has remained largely unknown.
The overall aims of this line of research are to i) identify non-cardiomyocyte players in sensing and orchestrating stress signals from mutant cardiomyocytes; ii) understand the mechanism(s) of these modulators in limiting or enhancing cardiac adverse remodelling, and iii) evaluate potential molecular or cellular targets for developing novel therapies.
Our current hypothesis is that cardiac innate (e.g. tissue macrophages) and adaptive (e.g. T and B lymphocytes) immune cells may play a role in modulating tissue homeostasis in HCM. Once activated by stress signals, some immune cells marshal extracellular matrix modulation (e.g. fibroblast activation/differentiation) and initiate local inflammation (e.g. recruitment of inflammatory cells). Chronically unresolved inflammation, leading to adverse remodelling, may be an important therapeutic target. To maximise tractability and therapeutic potential, our current focus is to establish the main cell types responsible for the immuno-inflammatory contribution to remodelling rather than to focus on the initiating steps or downstream events in fibroblasts.
With the support from a recent British Heart Foundation (BHF) programme grant, we outline our research activities as the following:
1) To establish the roles of different classes of immune cells, including of potentially protective cell types in HCM in mouse and patients;
2) To seek human genetic evidence of the role of innate and adaptive immunity in quantitative aspects of the HCM phenotype in patients;
3) To study the role of cardiac-specific autoantibodies in the dilated phase of human HCM.
Together with several world-leading immunologists in Oxford, we have generated some exciting preliminary data from a well-established HCM mouse model and started networking with local, national, and international colleagues in the clinic to map these immunological findings onto human HCM.
We are currently based at the Wellcome Centre for Human Genetics at the Old Road campus.