Chariman Emeritus (1998-2000)
Donald N. Pritzker Distinguished Service Professor Emeritus – 2011, Departments of Pathology, Biochemistry, Molecular Biology and the College
Department of Pathology
The University of Chicago
5841 S. Maryland Avenue
MC 1089, Room P-306
Chicago, IL 60637
The focus of our research program is on lipoprotein metabolism and atherosclerosis. Our major emphasis is on the role of the immune system and on the structure and function of the major apoproteins in HDL , apoA-I (243 amino acids) and apoE (299 amino acids). Both sets of studies are performed in mouse models.
In our first major focus, we have used immune deficient mice to probe the effect of the cells of the adaptive immune system on the development of atherosclerosis. Atherosclerosis is a chronic inflammation of the major blood vessels leading to such complications as heart attacks and stroke. We find that robust atherosclerosis can develop in the absence of the adaptive immune system, although for some blood vessels the adaptive immune system has important regulatory effects. Activation of the immune system depends usually on two signals; an antigen and one of a series of costimulatory molecules. We have complemented immune deficient mouse models of atherosclerosis with two subsets of immune cells B1 cells and NKT cells. The former secrete IgM antibodies to LDL modified by oxidation, while the latter recognizes lipid antigens, most of which have not yet been identified. While complementation with B1 cells has little influence on atherosclerosis, complementation with NKT cells promotes the development of atherosclerosis. The liver is enriched in NKT cells and NKT cells also influence lipoprotein metabolism. Current studies are directed at examining the mechanism of action of NKT cell on atherosclerosis and lipid metabolism and at identifying the lipid antigen activating these cells.
In collaboration with Dr. Yang-Xin Fu in Pathology Department we are also studying the influence of the TNF-related costimulatory molecule family LIGHT and lymphotoxin that signal through receptors present on hepatocytes and bone marrow derived cells. Overexpression of the ligand LIGHT suppresses the production of hepatic lipase in the liver leading to hyperlipidemia and accumulation of an apoE-enriched HDL particle. This is the first major finding of the mechanism for an effect of the immune system on lipoprotein metabolism and we are testing the hypothesis that NKT cells are particularly important for the lipoprotein effects. LIGHT and lymphotoxin also influence the development atherosclerosis, though not necessarily through their effects on lipoprotein homeostasis. Mice lacking or overexpressing these ligands and receptors and crossed with murine atherosclerosis models will allow for further mechanistic studies.
In our second research focus, we are interested in the regulation of HDL levels, subclasses, and function, especially as they relate to the atherosclerosis protective function of HDL . Human HDL has two major subclasses, designated HDL 2 and HDL 3 , while in mice there is only one HDL subclass. HDL 2 is larger and is thought to be more atheroprotective than HDL 3 . We know that apoA-I, the major apoprotein of HDL , is a critical determinant of HDL subclasses. We have generated human apoA-I mutants with affinity for either HDL 2 or HDL 3 and using a mouse model lacking HDL we hope to generate mice that have only one of these HDL subclasses so that we can test the proposition that HDL 2 is more atheroprotective. Recent work on HDL has given rise to study of apoA-I mimetic peptides having only18 amino acids that appear to be very effective as atheroprotective agents. We are studying variants of these mimetic peptides having two identical copies of the 18 amino acid peptide coupled by various linker sequences. These tandem peptides have different properties than the single 18 amino acid peptide and they are currently being tested for their respective effects on atherosclerosis and lipid parameters.