Primary AppointmentRadiology and Medical Imaging
PO Box 801339, 480 Ray C. Hunt Drive
Charlottesville, Virginia 22908
Cellular and genetic determinants of atherosclerosis and restenosis.
Genetics of Atherosclerosis and related disorders My primary research interest is in atherosclerosis, which is the cause of heart attack, stroke and peripheral arterial disease. Although mortality from atherosclerosis has had a decline in past few decades largely due to effective prevention programs, lipid lowering statin therapy and angioplasty/stenting, this disease continues to claim more lives than any other disease in the United States and other Western countries. Thus, there is a medical need to find new therapies for the disease. Inflammatory responses initiated by oxidation of LDL (bad cholesterol) trapped in the arterial wall is a key process driving the initiation, progression, and rupture of atherosclerotic plaques. However, there are no effective medicines available to intervene the inflammatory process due to lack of appropriate targets. We use powerful mouse genetics tools to search for genes and pathways acting at the level of arterial walls and have identified Rcn2 as a key regulator of cytokine production in endothelial cells. We have mapped dozens of novel genetic loci for atherosclerosis, including Ath29, Ath41, Ath42, Ath48, Ath49, Ath50, Cath1, Cath2, Cath3, Cath4, Cath5, Cath6, Cayth7, and Cath8. We are in the process of characterizing candidate genes for the loci. Diabetic patients have up to 4-fold increased risk for having incident cardiovascular events. We have mapped multiple loci for atherosclerosis that are overlapping precisely with loci for plasma glucose. We are testing the hypothesis that there exist genetic connections between the two important diseases. Development of effective imaging probes targeting macrophages Macrophages are involved in the development and progression of many important chronic inflammatory diseases, including atherosclerosis, asthma, inflammatory bowel disease, and type 2 diabetes. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is currently used to diagnose inflammatory diseases involving macrophages, but accurate quantitation of macrophages has been difficult due to background uptake by other cell types. We are testing more specific macrophage imaging agents that have little or no background binding to other cell types. The formyl peptide receptors (FPRs) are abundantly expressed on the surface of macrophages. We have successfully used a FPR receptor antagonist to detect macrophages in the pancreas of mice. We are in the process of designing, synthesizing and evaluating imaging gents that can be applied to humans.