Department of Cellular and Molecular Medicine
Martha K. Cathcart, Ph.D.
Lerner Research Institute
9500 Euclid Avenue
Cleveland, Ohio 44195
The focus of our research is on defining the mechanisms responsible for LDL and lipid oxidation during the activation of human monocytes (HM) and to study the role of lipids in regulating HM activation and migration into sites of inflammation. These events contribute to lipid accumulation in atherosclerosis and mediate tissue injury in pathologic settings. There are three main projects in the laboratory. The first project investigates the regulation of an enzyme complex called NADPH oxidase that is essential for the production of the oxygen radical superoxide anion. Superoxide anion contributes to unregulated uptake of LDL into macrophages and atherosclerotic lesion formation. Our studies are defining the roles for phospholipases, small G-proteins and kinases in oxidase activation. In project two, we are studying 15-lipoxygenase (LO) gene expression during HM activation. We were the first to demonstrate the presence of LO products in human atherosclerotic tissue. Our goal is to understand the cytokine-mediated induction of expression of this enzyme. The third project is focused on understanding the role of phospholipases and kinases in regulating HM chemotaxis in response to MCP-1 a chemokine that attracts monocytes into the vessel wall in atherosclerosis. In summary, we are studying a variety of regulatory pathways and defining their contributions to modulating the activity of HM in inflammatory responses. Our findings will suggest new approaches for inhibiting these processes and limiting the progression of atherosclerosis and other chronic inflammatory diseases.
In other words ...
Our research is focused on understanding the molecular pathways that control chronic inflammation. Our recent work has elucidated new biochemical pathways that control white blood cell movement from the blood into inflamed tissues and regulate their activation pathways leading to altered production of reactive oxygen species and bioactive lipids. In these studies we have also discovered a novel approach for treatment of glioblastoma and have focused on new molecules involved in resolving inflammation.
1: Bhattacharjee A et al. Hck is a key regulator of gene expression in alternatively activated human monocytes. J Biol Chem. 2011, 286(42):36709-23.
2: Elsori DH et al. Protein kinase C delta is a critical component of Dectin-1 signaling inprimary human monocytes. J Leukoc Biol. 2011, 90(3):599-611.
3: Hsi LC et al. Silencing IL-13Ralpha2 promotes glioblastoma cell death via endogenous signaling. Mol Cancer
Ther. 2011, 10(7):1149-60.
4: Yakubenko VP, et al. AlphaM-Beta2 integrin activation prevents alternative activation of human and murine macrophages and impedes foam cell formation. Circ Res. 2011;108(5):544-54.
5: Bhattacharjee A, et al. Monocyte 15-lipoxygenase gene expression requires ERK1/2 MAPK activity. J Immunol. 2010;185(9):5211-24.
6: Cathcart MK. Signal-activated phospholipase regulation of leukocyte chemotaxis. J Lipid Res. 2009;50 Suppl:S231-6.
7: Mishra RS, Carnevale KA, Cathcart MK. iPLA2beta: front and center in human monocyte chemotaxis to MCP-1. J Exp Med. 2008, 18;205(2):347-59.