The Hammad laboratory is interested primarily in lipoprotein-related research. Recently, our focus has been on investigating the sphingolipid signaling mechanisms which mediate the survival of foam cells (lipid laden macrophages) and their sustained cell activation in response to modified lipoproteins and lipoprotein-immune complexes. The transformation of macrophages into foam cel ls is a critical event in the development of atherosclerosis and defining mechanisms mediating foam cell formation and determining the role of foam cells in the pathology of atherosclerosis is an area of great clinical relevance. Our goal is to uncover targets in the signaling pathway such as receptors and/or sphingolipids that can have therapeutic implications for blocking cytokine release and prevention of vulnerable atherosclerotic plaques. Macrophages internalize oxidized LDL immune complexes (oxLDL-IC) via the Fc-y receptor and transform into activated foam cells. Our data demonstrated that exposure of human monocytic cells to oxLDL-IC leads to increased cell survival compared to oxLDL alone. We examined the effect of oxLDL-IC on sphingosine kinase 1 (SK1), an enzyme implicated in mediating pro-survival and inflammatory responses through the generation of the signaling molecule sphingosine-1-phosphate (S1P). Intriguingly, oxLDL-IC, but not oxLDL alone, induced an immediate translocation and release of SK1 into the conditioned medium. This finding indicates that S1P may be generated extracellularly in response to modified LDL immune complexes and may therefore promote cell survival and prolong cytokine release by activated macrophages. Our goal is to uncover mechanisms by which oxLDL-IC suppress apoptosis of foam cells, and reveal specific targets in the signaling pathway that can have therapeutic implications for blocking cytokine release and to prevent formation of vulnerable plaques.
Another area of interest is the role of modified lipoproteins in diabetic vascular complications including nephropathy. We have investigated the effects of hypercholesterolemia on the development of diabetic complications in a genetically modified hypercholesterolemic mouse made diab etic with streptozotocin. The mouse is a double knockout for the LDL receptor and the editing of the apoB mRNA (LDLr-/- Apobec -/-). In this animal model, we found that the combination of hypercholes terolemia and diabetes resulted in a significant lipid accumulation in the tubular basement membrane, which could have contributed to the albuminuria. We also published the first report on the mouse lipoprotein subclass profile using Nuclear Magnetic Resonance (NMR).
Another area of research, with which I am involved and collaborating with Dr. W.S. Argraves in the department, is the function of the newly discovered HDL receptor, Cubilin, in mediating uptake, degradation and transcytosis/exocytosis of HDL. Cubilin is expressed in the renal proximal tubule, intestine, and yolk sac endoderm. Our goal is to determine the physiological significance of cubilin-mediated renal uptake of filterable forms of HDL to HDL homeostasis. A decreased level of plasma HDL is a major risk factor for coronary atherosclerosis.