Xiaoke Ge, MSc

Novel genetic targets to treat atherosclerotic cardiovascular disease

Cardiovascular diseases (CVD), mainly caused by atherosclerosis, have become a health problem all over the world that need to be solved urgently. One of the most important risk factors for atherosclerosis is dyslipidemia which causes accumulation of lipids in the arterial wall, subsequently triggering a pro-inflammatory response after activation of macrophages. However, currently available lipid-lowering medication can only partially prevent mortality and morbidity due to CVD, and novel pharmacological modulators of lipid/lipoprotein metabolism are eagerly awaited to better treat dyslipidemia and therefore atherosclerosis.

My current work focuses on two novel targets: 24-dehydrocholestreol reductase (DHCR24) and ATP binding cassette transporter A6 (ABCA6).

DHCR24 mediates the conversion of desmosterol, an endogenous liver X receptor alpha agonist, into cholesterol, and treatment with desmosterol has been shown to reduce atherosclerosis development by attenuating macrophage activation. Therefore, we will evaluate the effect of unique in-house small molecules to increase desmosterol by inhibiting DHCR24 on lipid metabolism, inflammation and atherosclerosis development.

ABCA6 belongs to a group of transmembrane proteins mediate the transport of various molecules such as lipids. Our preliminary data show that the in-depth plasma metabolomics profile associated with a driving ABCA6 variant is highly atherogenic, evidenced by the increased levels of LDL and IDL particles. As data on the biological function of ABCA6 in lipid metabolism are scarce, we aim to investigate the role of ABCA6 on lipid metabolism and atherosclerosis development.

Collectively, these studies will elucidate the potential of DHCR24 and ABAC6 to serve as a promising therapeutic targets for reducing CVD risk.