1. The pathomechanisms of atherosclerotic plaque formation, instability and novel therapies
We are interested in using various animal models of atherosclerosis, incl. ApoE-/-, LDLR-/-, AAV8-PCSK9-D377Y injection etc to explore new disease relevant targets in the pathogenesis of atherosclerosis. Systematic analysis of plaque formation in en face aorta, aortic sinus/root, and innominate artery as well features of plaque vulnerability (necrotic core area, fibrosis cap thickness, neovascularization, intraplaque hemorrhage and collagen content) will be assessed. Future targeted therapies using genetic means and pharmacological modifiers will be used to provide the proof-of-concept. High content and high throughput compound screening will be used to assist new drug discovery from natural sources or drug repurposing. The development of new compound disease models that mimic human disease pathology is another focus.
2. The role of vascular inflammation and cell metabolism in cardiometabolic diseases
We are intrigued by how vascular inflammation (leukocyte adhesion/extravasation into blood vessel) initiate and perpetuate atherosclerotic cardiovascular diseases. Epigenetic mechanisms involving DNA methylation, histone modification, RNA methylation, miRNA, long non-coding RNA (lncRNA) and circular RNA-based mechanisms will be pursued. The novel mechanisms of traditional and new cardiometabolic risk factors in vascular function, incl. oxidized LDL, cholesterol crystal, advanced glycation endproducts (AGE) etc on vascular function will be also be interested. In terms of the important role of cell metabolism, incl. glucose, lipid, fatty acid, acetyl-CoA and amino acid in regulating endothelial function, the role of key enzymes/targets in cell metabolism in cardiometabolic diseases will be evaluated.
3. The role of mechanical force in endothelial cell behaviour, function and cardiometabolic diseases
Atherosclerosis is a chronic inflammatory disease with a mechanical molecular basis. Endothelial cells are exposed to various types of mechanical forces, incl. shear stress. Endothelial cells align parallel to the direction of blood flow. The endothelial cell and smooth muscle cell morphology in different regions of blood vessel varies according to different patterns of blood flow. Among different tissues, or even within the same tissue, endothelial cells bears tremendous heterogeneity. It remains unclear how local hemodynamic mileu regulates endothelial heterogeneity, function and behaviour, as well as cell-cell interactions. We will utilize advanced biotechnologies, including microfludic, transcriptional profiling, single cell RNA-sequencing, ATAC-seq, Hi-C, ribosome-profiling etc, to probe this question.
About the lab
The Xu laboratory studies the molecular and cellular biology and therapies of cardiometabolic disease, with an emphasis on inflammation, advanced atherosclerosis and lipid/glucose metabolic disorders, and the mechanistic links between these processes.
Research keywords: Vascular biology, cardiovascular disease, metabolic disease, drug screening, biomechanics, shear stress, therapy