Assistant Professor of Pediatrics

Research Interests: Cholesterol homeostasis

Atherosclerosis leads to stroke and coronary artery disease, the leading cause of death in the Western societies. Current therapeutic strategies to prevent atherosclerosis are primarily based on the use of lipid-lowering drugs, statins, which inhibit 3-hydroxy-3-methyl-glutaryl-CoA reductase and increase low-density-lipoprotein (LDL) receptor expression, subsequently decreasing de-novo cholesterol synthesis and serum LDL cholesterol levels. The treatment of patients with statins reduces cardiovascular events by about 20-40%, indicating an important need for new therapies. The goal in my laboratory is to identify novel proteins relevant to cardiovascular disease and the translation of this knowledge to develop novel therapeutics with improved efficacy. 

Section one: Investigation of cholesterol homeostasis in macrophages.

The excessive accumulation of LDL-derived cholesterol by monocyte-derived macrophages in the artery wall leads to foam cell formation, a key factor in the initiation and progression of atherosclerosis. Macrophages cannot limit the uptake of cholesterol and cannot degrade cholesterol. Thus, high-density lipoprotein (HDL)-mediated macrophage reverse cholesterol transport (RCT) plays a critical and essential role in maintaining cholesterol homeostasis in macrophages. ATP-binding cassette (ABC) transporters, such as ABCA1 and ABCG1, play an important role in the first and rate-limiting step of macrophage RCT through exporting cholesterol from the cells. However, the mechanism of ABC transporters-mediated transport of lipids and sterols has not been definitively established. This absence of basic knowledge will dramatically delay the future design of novel therapeutic agents that can prevent and treat atherosclerosis. Thus, studies in my lab are focusing on elucidating how ABC transporters mediate sterol efflux to HDL and prevent formation of foam cells using various modern techniques in biochemistry, cell and molecular biology.

Section two: Identification of novel proteins important for regulating LDL-cholesterol homeostasis in circulation.

The LDL receptor (LDLR) in the liver is the protein primarily responsible for removal of LDL cholesterol from the circulation. Mutations in the LDLR and the ligand for the LDLR (apolipoprotein B-100 (apoB-100)) all cause autosomal dominant hypercholesterolemia (ADH). ADH is an inherited disorder associated with elevated plasma LDL-cholesterol levels, leading to increased risk in coronary heart disease and mortality. Recently, a third form of autosomal-dominant hypercholesterolemia was identified that is caused by gain-of-function mutations in proprotein convertase subtilisin/kexin-type 9 (PCSK9). The contribution of mutations in the LDLR, apoB-100 and PCSK9 to ADH is approximately 67%, 14%, and 2.3% respectively. Thus, the genetic origin of about one in six ADH patients is still unknown. We are utilizing a wide range of modern techniques in biochemistry, cell biology, and molecular biology to search for novel proteins that are involved in regulating LDL cholesterol homeostasis in circulation.