The crux of many health conditions lies in the blood vessels. Stroke and cardiovascular diseases are the leading causes of mortality globally. Advances in omics techniques have discovered many genetic variations and protein markers that are associated with vascular diseases. However, the lack of biological insights has impeded their translation into the intended benefit of therapy and diagnostics. Our overarching goal is unravel the functional basis of disease biomarkers, so as to inform strategies for restoring blood vessel health. The key thrusts of our research are:
A key challenge of interpreting risk variants from genome wide association studies is that most variants do not encode genes. Emerging evidence suggests that non-coding variants may reside in regulatory elements or disrupt transcription factor-DNA binding. Also, they may influence the activity of other gene-coding regions through long range chromatin interactions, leading to phenotypic differences. We are working on the genotype-to-phenotype basis of some vascular disease-associated variants, in order to elucidate how they act through a wider complex network to impact on the genes with direct relevance to the illness.
Stroke survivors have increased risk of recurrent vascular complications, underscoring a critical role of blood vessel health in stroke management. Immune cells and vascular progenitor cells show characteristic changes in their gene expressions and phenotypes in response to vascular injury. We are developing prognostic biomarkers that are well-grounded on the function of these blood-borne cells. Deep-dive analysis of patient-derived cells would reveal mechanistic differences in ‘susceptible’ versus ‘protective’ individuals.
Human-Relevant Disease Models
There are well-studied morphological, biochemical and phenotypical heterogeneities in our blood vessel system. Using the human pluripotent stem cell (hPSC) technology, we have invented techniques to derive vascular smooth muscle and endothelial cells, resembling those found in the brain and heart arteries. Such resources open the door to creating personalised vascular models that are amenable to comprehensive phenotypic assessment and gene editing. The hPSC-based vascular models also enables far-reaching experimental strategies e.g. drug/inhibitor screening to facilitate the development of novel therapeutics.