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Research Description:
Dr. Vogt’s major research interest is the discovery of new therapeutic agents for diseases related to cell proliferation and intracellular signaling. Specific targets of interest are the mitogen-activated protein kinase phosphatases (MKPs), cellular enzymes involved in cancer and inflammation that have thus far eluded discovery efforts. An important part of his research is the development of analysis tools to increase information content of biological assays and to enable small molecule drug discovery screening in whole organisms. It is his hope that the combination of high information content assays with whole organism models of disease will result in higher quality candidate compounds for drug development. Dr. Vogt’s target-based discovery efforts center around mitogen-activated protein kinase phosphatases or MKPs. One MKP in particular, termed DUSP-1 or CL100, appears to be a mediator of the malignant phenotype. MKP-1 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, either alone or in combination with clinically used antineoplastic agents. The search for small molecule inhibitors of MKP-1 has been challenging due to a lack of structural guidance for inhibitor design, ambiguities associated with in vitro assays for phosphatase activity, and the absence of definitive assays to probe MKP-1 inhibition in the context of the living cell. By developing an image-based, definitive cellular assay for MKPs, which he has termed “chemical complementation”, Dr. Vogt has circumvented many of the challenges associated with MKP inhibitor discovery, screened several thousand small molecules for MKP inhibition in intact cells, and identified several cell-active inhibitors of MKP-1 and MKP-3. Future work will encompass discovery of multiple classes of MKP inhibitors, refinement of their structures and biological activities, evaluation of their mode of inhibition, and their credentialing as potential therapeutic agents. Recently, Dr. Vogt has extended the concept of chemical complementation to collaborations with members of the zebrafish community on the discovery of inhibitors of MKP-3. Dr. Vogt’s second focus is the continued development of novel drug discovery tools that enhance the information content of small molecule screens. Over the past five years, he has been involved in the establishment of the University of Pittsburgh Drug Discovery Institute (UPDDI) as one of only a handful of academic centers with high-content analysis (HCA) capabilities. HCA is an analysis tool to acquire, analyze, and manage multi-dimensional information about target activity and spatial distribution from individual cells. Our emphasis on HCA has substantially contributed to the UPDDI becoming one of nine national screening centers funded through the NIH roadmap initiative on Molecular Libraries and Imaging. Dr. Vogt’s research has contributed to the center four R03 funded high-content screens (two for MKPs, one for microtubule stabilizing agents, and one for autophagy), which he is currently running on 200,000 small molecules from an NIH compound collection. A natural extension of Dr Vogt's prior HCA work is the expansion of image-based analysis to whole organisms such as zebrafish. This work is based upon the observation that advances in high-throughput screening and laboratory automation have substantially improved the speed of target-based drug discovery but that these efforts have not resulted in increased research productivity. An increasingly popular sentiment is that better models are needed to improve the quality of new drug candidates, and it has been proposed that whole organisms could provide such models. Currently, however, there is no animal model that is compatible with the contemporary paradigm of drug discovery encompassing rapid screening of large compound collections. The zebrafish is an animal model that might fill this void. The NIH is currently supporting a collaboration with Neil Hukriede and Michael Tsang (Department of Molecular Genetics and Biochemistry) aimed at developing novel image-based methods to analyze fluorescent transgenic zebrafish embryos. Of particular interest is an intelligent image analysis method termed Cognition Network Technology (CNT). CNT is different from other image analysis methods in that it processes image information in an object oriented fashion, thereby emulating human cognitive processes. With this approach, Dr. Vogt is able to detect zebrafish embryos in multiwell plates regardless of orientation and to detect and quantify structures of interest within specific parts of the zebrafish embryo. An example is the automated detection and quantification of intersegmental blood vessels in the dorsal trunk of the zebrafish as measure of in vivo angiogenesis (Figure 2). Dr. Vogt developed a rule set that successively identified the entire outline of the embryo and defined regions of interest such as aorta (magenta), head (brown), yolk and yolk tube (yellow), and dorsal area (dark green). This context-based segmentation permitted the isolation and quantification of intersegmental blood vessels (red) without interference from surrounding areas. Because CNT can identify complex zebrafish embryonic structures regardless of orientation, the embryo can be arrayed randomly into any position and CNT will identify these distinct structures. Currently Dr. Vogt is working to generate a rule set that will identify the GFP expression in specific parts of the brain of a transgenic animal expressing an Fgf reporter (Tg(Mkp3:d2eGFP).
Education:
BS (Pharmacy), University of Hamburg, Germany, 1985.
PhD (Pharmaceutical Chemistry), University of Hamburg, 1990.
Important Publications:
- Vogt A, H Codore, BW Day, NA Hukriede and M Tsang. Development of automated imaging and analysis for zebrafish chemical screens. JoVE 40. doi:10.3791/1900. http://www.jove.com/index/Details.stp?ID=1900, 2010
- Molina G, A Vogt, A Bakan, W Dai, PQ de Oliveira, W Znosko, TE Smithgall, I Bahar, JS Lazo, BW Day and M Tsang. Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages. Nat Chem Biol 6:680-687, 2009
- Vogt A, A Cholewinski, X Shen, SG Nelson, JS Lazo, M Tsang and NA Hukriede. Automated image-based phenotypic analysis in zebrafish embryos. Dev Dyn 238:656-663, 2009
- Raccor BS, A Vogt, RP Sikorski, R Balachandran, K Montgomery, Y Shin, Y Fukui, W-H Jung, DP Curran and BW Day. Cell-based and biochemical structure-activity analyses of analogues of the microtubule stabilizer dictyostatin. Molecular Pharmacology 73 (3):718-726, 2008
- Vogt A, PM McDonald, A Tamewitz, RP Sikorski, P Wipf, JJ Skoko and JS Lazo. A cell-active inhibitor of mitogen activated protein kinase phosphatases restores paclitaxel-induced apoptosis in dexamethasone-protected cancer cells. Molecular Cancer Therapeutics 7 (3):330-340, 2008
- Vogt A and JS Lazo. Chemical complementation: A definitive phenotypic strategy for identifying small molecule inhibitors of elusive cellular targets. Pharmacology & Therapeutics 107:212-221, 2005
- Vogt A, A Tamewitz, J Skoko, RP Sikorski, KA Giuliano and JS Lazo. The benzo[c]phenanthridine alkaloid, sanguinarine, is a selective, cell-active inhibitor of mitogen-activated protein kinase phosphatase-1. Journal of Biological Chemistry 280 (19):19078-19086, 2005
- Vogt A, KA Cooley, M Brisson, MG Tarpley, P Wipf and JS Lazo. Identification of DSPase inhibitors by high content screening in intact mammalian cells. Chemistry & Biology 10:733-742, 2003
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