My laboratory is interested in understanding the expression and regulation of enzymes involved in arachidonic acid (lipid) metabolism, and their role in the development of cardiovascular diseases. The current research interests in my laboratory are described below. 1. The paraoxonase (PON) gene family consists of three family members, PON1, PON2 and PON3. PON genes are implicated in the pathogenesis of several inflammatory diseases including atherosclerosis. Our long-term goal is to understand the physiological role of PON2 and PON3 proteins. Recent findings lead us to hypothesize that PON2 protein may play a novel role in host defense and innate immunity by protecting against gram-negative microbial infection and the pathogenesis of inflammatory diseases such as atherosclerosis. We are using PON2-deficient and PON2Tg mice to test this novel hypothesis for the physiological role of PON2. 2. Defining the cardiovascular effects of COX-2-selective inhibitors has taken an increasing clinical relevance due to their recall following reports of cardiovascular side effects from their use. To determine the mechanism of COX-2 in the development of atherosclerosis, we have generated conditional COX-2 transgenic and knockout mice (together with our collaborators at UCLA). These mice are being studied to define the molecular mechanisms behind the therapeutic disadvantages of COX-2 selective inhibitors. 3. The anti- or pro-inflammatory nature of HDL function is a more sensitive indicator of the presence or absence of atherosclerosis than HDL cholesterol levels. Although a number of proteins and enzyme activities have been associated with HDL, little is known of what particular protein profiles constitute HDL function. Our laboratory utilized state of the art proteomics methodologies and identified protein signatures that distinguish pro-inflammatory HDL from anti-inflammatory HDL in animal models of atherosclerosis. We are currently characterizing and validating these proteins for i) the development of novel biomarkers for the early detection of atherosclerosis and ii) understanding the mechanisms that participate in the formation of pro-inflammatory HDL.