My target-based discovery efforts center around mitogen-activated protein kinase phosphatases or MKPs. One MKP in particular, termed MKP-1/DUSP-1/CL100, appears to be a mediator of the malignant phenotype. MKP-1/DUSP1 is overexpressed in many human tumors and can protect cells from apoptosis caused by DNA damaging agents or cellular stress, suggesting that inhibitors of MKP-1 might find applications as novel target-based antineoplastic therapies.  A related phosphatase, MKP-3/DUSP6, mediates ischemic injury in the heart.  In adult mice, overexpression of MKP-3/DUSP6 potentiates ischemic injury whereas deletion of MKP-3/DUSP6 protects the heart from ischemic insult and prevents scarring, suggesting that inhibition of MKP-3/DUSP6 by small molecules may represent a novel pharmacologic strategy to protect the myocardium from ischemic injury.  The search for small molecule inhibitors of MKPs has been challenging due to a lack of structural guidance for inhibitor design, the abundant use of uninformative in vitro assays for phosphatase activity, and the absence of definitive assays to probe MKP inhibition in the context of the living cell or a whole organism.  With the help of collaborators in the Departments of Developmental Biology,  Computational Biology, and Pharmaceutical Sciences, I am currently using a combination of high-content analysis, transgenic zebrafish, and computational modeling to engineer novel approaches to MKP inhibition.

My second focus is the continued development of novel drug discovery tools that enhance the information content of biological assays. Over the past five years, I have been involved in the establishment of the University of Pittsburgh Drug Discovery Institute (UPDDI) as one of the first academic centers with high-content analysis (HCA) capabilities. As a founding member of the UPDDI I am actively pursuing collaborative discovery projects with Neil Hukriede (kidney regeneration), Michael Tsang (FGF signaling and MKP inhibition), Billy Day (microtubules) , Tom Smithgall (HIV-Nef), Lin Zhang (PUMA), and Keren Hulkower, Platypus Technologies (cell migration).

A natural extension of my work is the expansion of image-based analysis to whole organisms such as zebrafish. The zebrafish embryo is a particularly attractive candidate for contemporary drug discovery because it is small, easily kept and obtained, and optically transparent.  The NIH is currently supporting a collaboration with Neil Hukriede and Michael Tsang (Department of Developmental Biology) aimed at developing novel image-based methods to analyze fluorescent transgenic zebrafish embryos. Of particular interest is an artificial intelligence-based method termed Cognition Network Technology (CNT) that emulates human cognitive processes.  My ultimate goal is to establish the UPDDI as center for zebrafish dug discovery.