Lab Research Focus
The focus of our laboratory is to understand how bioactive lipids produced by oxidative and enzymatic modification of lipoproteins and cellular membranes regulate inflammatory and immune processes associated with atherosclerosis and autoimmunity.
Background
It is widely recognized that therapeutic augmentation of high-density lipoprotein (HDL) levels can afford significant protection against atherosclerosis in individuals with traditional risk factors for cardiovascular disease. In addition to its role in lipid and cholesterol transport, anti-inflammatory action and anti-oxidant activity are considered to be major functional properties of HDL accounting for its protective effects against atherosclerosis. These functional properties of HDL are mediated by its compliment of associated proteins (such as apolipoprotein-A1) and enzymatic activities (including paraoxonase-1 and PAF-AH) which collectively limit the accumulation of biologically active lipids and the production of pro-inflammatory oxidized phospholipids. Certain chronic inflammatory diseases are associated with the development of dysfunctional HDL characterized by reduced HDL levels, impaired anti-oxidant and anti-inflammatory properties, and altered HDL-associated enzymatic activities. The development of dysfunctional HDL in such diseases may therefore contribute to increasing risk for atherosclerosis. For example, premature atherosclerosis is a major cause of morbidity and mortality in certain autoimmune diseases, including systemic lupus erythematosus (SLE), and impairment of HDL may be a major contributing factor. However, there is increasing evidence that in addition to its protective role in atherosclerosis, HDL may also down-modulate immune processes involved in the development of autoimmunity. For example, the cholesterol transport function of HDL may limit excessive cholesterol accumulation in immune cells to prevent aberrant hyper-proliferative lymphocyte responses, while its anti-inflammatory effects may modify the development and/or activity of auto-reactive lymphocytes and other regulatory immune cell-types.
Projects
A major focus of our laboratory is to determine whether therapeutic modulation of HDL levels and function in SLE is not only beneficial with respect to reducing atherosclerosis risk, but also efficacious as a strategy to attenuate autoimmunity and improve life-threatening pathological manifestations of autoimmune disease. Emphasis is placed on determining how the development of autoimmunity in SLE-prone mice affects HDL and establishing the mechanisms responsible. Recent findings by our laboratory in SLE-prone mice corroborate findings in human SLE patients with respect to the potential involvement of anti-apolipoprotein-A1 auto-antibodies in mediating certain aspects of HDL dysfunction. We are also testing the efficacy of therapeutic strategies (such as administration of apolipoprotein-A1 mimetic peptides) aimed at improving HDL function and/or raising HDL levels in SLE-prone mice.
Another major area of interest in our laboratory is to determine the role of a lipid-sensitive G protein-coupled receptor (G2A) in atherosclerosis and HDL metabolism. G2A is expressed by multiple immune cell-types as well as hepatocytes. We found that the absence of G2A in hypercholesterolemic mice suppressed atherosclerosis and that this effect was associated with an elevation in HDL levels that may be mediated by increased hepatic apolipoprotein-A1 secretion. Current projects seek to establish the mechanisms underlying these effects of G2A at the cellular and molecular level.
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