PLK1, a potential novel therapeutic target for lupus

In a recent activity-based kinome screening in the spleen of murine lupus, we identified several important kinases exhibiting increased activities compared to normal controls. Among these, Polo-like kinase 1 (PLK1) emerges as a novel target in murine lupus. PLK1 is a serine/threonine kinase, and PLK1 inhibition could down-regulate TNF-a production in monocytes. PLK1 inhibition could also downregulate LPS-induced cytokine production and activation of downstream signaling cascade. Importantly, PLK1 could impact signaling pathways such as PI3K/mTOR, NF-kappaB and CDK1 which are upregulated in murine lupus. Our preliminary data suggest that PLK1 blockade of murine lupus ameliorated splenomegaly, reduced anti-dsDNA antibody, proinflammatory cytokine, proteinuria and BUN levels, and improved renal pathology in murine lupus. Taken together, PLK1 might be an attractive therapeutic target in lupus, not only for dampening lymphoproliferation but also for controlling inflammation. We propose: 1. To explore the molecular and cellular basis by which PLK1 impacts cell proliferation, anti-dsDNA antibody production and proinflammatory cytokine production in murine lupus nephritis; 2. To test if PLK1 inhibition can ameliorate disease in murine lupus after disease onset (therapeutic study); 3. To determine if PLK1 expression and phosphorylation are elevated in PBMCs from lupus patients, and how PBMCs respond to PLK1 inhibition.