Researchers in the Boisvert Lab are focused on exploring immunity and inflammation in the pathogenesis of atherosclerosis.
Top (l-r): William Boisvert, Ph.D. (Associate Professor), Kosal Seng, B.S. (Medical Student), Trevor Grace, B.S. (Medical Student), Eric Collier, B.S. (Research Assistant); Bottom (l-r): Svenja Meiler, Ph.D. (Postdoctoral Fellow), Emma Toulmin, Ph.D. (Postdoctoral Fellow), Sara McCurdy, B.S. (Graduate Student), Yvonne Baumer, Ph.D. (not pictured)
1. IL-10 in Macrophage Foam Cell Formation
(click on image to enlarge)
We have studied the inflammatory aspect of atherosclerosis through immunomodulation by IL-10, a prototypic anti-inflammatory cytokine. Selective overexpression of IL-10 by activated T lymphocytes in a mouse model of atherosclerosis resulted in significant reduction in atherogenesis compared to control mice. More recently we have overexpressed IL-10 in macrophages by infecting hematopoietic stem cells with IL-10-expressing retrovirus and injecting them into irradiated mice that result in long-term overexpression of IL-10. This procedure significantly reduced atherosclerosis mainly by facilitating cholesterol uptake and efflux in the lesion macrophages. We are continuing this work and expressing other genes using similar technique to study other inflammation-related processes.
2. Macrophage Migration Properties
One of the most important cell types in the pathogenesis of atherosclerosis is the macrophage. Our lab has demonstrated in the past that the chemokine and its receptor, IL-8 and CXCR2, play an important role in the chemotaxis of macrophages to the atherosclerosis-prone vascular wall. We are continuing to investigate the migratory properties of these cells into the atherosclerotic vessel wall. We have found recently that the deficiency of a cell surface sialoglycoprotein leads to reduced atherosclerosis by limiting the migration of monocytes into the lesion sites. In addition to cell surface glycoproteins, we are also investigating the involvement of selectin ligands and other adhesion molecules on macrophage motility in hopes of attenuating atherogenesis by targeting these molecules on monocytes.
3. Role of ROCK in Atherosclerosis
We are currently engaged in studies to assess the role of Rho kinase (ROCK) in immune function as well as in immune-mediated atherosclerosis. We have found recently that ROCK can have a potent influence on various functions of T lymphocytes and monocyte/macrophages. A comprehensive in vivo study has just been completed in which various deficiency models of ROCK resulted in significant reduction in atherogenesis. We are actively studying the mechanisms by which ROCK modulates various atherogenic functions of leukocytes. We are also examining the specific roles of ROCK1 and ROCK2 isoforms by using conditional knockout mice that are deficient in either ROCK1 or ROCK2 in various cell types of the immune system.
4. Inflammasome in Macrophage Function
We have recently set up a collaborative project with Dr. Richard Flavell of Yale University, to study the role of inflammasome in macrophage function. Dr. Flavell has generated the NALP3-/- mice that do not express functional inflammasome and has shared the mice with us to use for this project. Because of the involvement of inflammasome in many of the inflammatory functions of macrophages, this project should yield many exciting results related to the macrophage function in general as well as the pathogenesis of atherosclerosis.
5. CD98 in Migration of Smooth Muscle Cells
In collaboration with Dr. Mark Ginsberg of UCSD, we have begun to investigate the role that CD98 plays in the migration of vascular smooth muscle cells (VSMC) during atherosclerosis. Dr. Ginsberg has generated mice with CD98 deficiency specifically in the VSMC and has provided us with the mice for our study. The migration and proliferation of VSMC is an important aspect of the progression of atherosclerosis. Any mechanistic insight into proteins that regulate this process will be valuable to devise measures to combat the migration of VSMC during atherosclerotic development.
6. MicroRNA regulation
We have identified several microRNAs that are important regulators of macrophage lipid homeostasis. We are working to determine the role of each one of these miRNAs and what aspect of lipid uptake and/or lipid efflux they participate in.
Dr. William Boisvert