HigH-Content AnAlysis

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Cambridge Healthtech Institute’s TENTH Annual January 8-11, 2013 High-Content Analysis Anniversary 3:15-4:15 Refreshment Break in the Sponsored by Exhibit Hall with Poster Viewing Novel Biosensor Assays for Screening 4:15-4:40 Development, Optimization and Validation of an HCS Biosensor Assay to Identify Compounds that Disrupt AR-TIF2 Protein-Protein Interactions Paul A. Johnston, Ph.D., Research Associate Professor, Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh High Transcriptional Initiation Factor 2 (TIF2) coactivator expression levels are associated with prostate cancer (CaP) recurrence after androgen ablation therapy (AAT). We will describe the development and optimization of a novel high-content image-based AR-TIF2 protein-protein interaction biosensor (PPIB) assay that exploits features of protein targeting to organelles, AR and TIF2 functional domains, and fluorescent reporters to generate positional biosensors to measure and quantify the interactions between AR and TIF2 in cells. We will validate the performance of the AR-TIF2 PPI HCS assay by screening the LOPAC and NIH Clinical Collection compound libraries in two distinct formats; to identify compounds that can either block the formation or that can disrupt established AR-TIF2 PPI complexes. 4:40-5:05 Novel Approaches to High-Content Imaging of Insulin Receptor Trafficking, Insulin Signaling and Endosomal Calcium Signaling James Johnson, Ph.D., Associate Professor, Cellular and Physiological Sciences, University of British Columbia We have generated insulin receptor reporters that do not impair signaling function in cells and will present data on insulin receptor trafficking and signaling in pancreatic beta-cells. We have developed the first calcium biosensor capable of measuring calcium in the lumen on the endosome and will present our analysis of the role for endosomes as dynamic calcium buffers. We present multiplexing approaches to generating rich data sets reporting on insulin signaling. 5:05-5:30 High-Content Screening for Small Molecule Inhibitors of HIV Nef Andreas Vogt, Ph.D., Associate Professor, Drug Discovery Institute, University of Pittsburgh The HIV-1 accessory protein Nef is essential for high-titer viral replication and AIDS progression. The cellular activities of Nef are critically dependent on a variety of protein-protein interactions, including formation of Nef oligomers. Nef mutations that interfere with oligomerization prevent HIV replication in cell culture, suggesting that the Nef oligomerization interface is a rational target for Nef-directed anti-HIV therapy. In this talk, I will present the development and validation of a high-content, bimolecular fluorescence complementation assay for Nef dimerization inhibitors. HCS at NCATS 5:30-5:55 Supporting Drug Discovery and Reposition in NCATS Using HCS Technology Zhuyin (Julie) Li, Ph.D., Biology Team Leader, Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, NIH The mission of the newly created National Center for Advancing Translational Sciences (NCATS) in NIH is to catalyze the generation of innovation methods and technologies that will enhance the development, testing, and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions. This presentation will highlight successful applications of HCS in target validation, compound screening, MOA study, toxicity investigation and drug repositions in NCATS. High-Content Image and Data Analysis (continued) 4:15-4:40 Using New Cell Dyes and Automated Image Processing to Evaluate Cellular Responses to Small Molecules David W. Andrews, Ph.D., Director and Senior Scientist, Biological Sciences, Sunnybrook Research Institute, Toronto; Professor, Biochemistry, University of Toronto Here we describe a simple approach to quantify the responses in adherent cells to small molecules based on multivariate analysis of cells stained with new mix and read dyes. These dyes are non-toxic, non-fluorescent in water and available in several emission/excitation wavelengths compatible with existing HCA instruments. We compare multivariate analysis and clustering with more traditional measures of analysis and find that it provides high Z’ sensitivity and specificity resulting in improved classification in screening. 4:40-5:05 A Label-Free Random Cell Motility Assay Based on Image Correlation Spectroscopy Michael Prummer, Ph.D., Scientist, High-Content Screening, F. Hoffmann-La Roche AG Cell migration is central to embryonic development, wound healing, inflammation, and cancer. Sparse metastatic cells or T-cells show isotropic and random motion, which is difficult to characterize with classical tools like scratch assays. We use image correlation spectroscopy (ICS) to quantify the speed and mode of random cell motility without labeling, identification or trajectory reconstruction. ICS offers a toolbox to analyze free, directed, hindered, or confined random walks. The random motility (RAMOT) assay is validated using THP1 immune cells, cytoskeleton modulators and Monte-Carlo simulations. Combining ICS and HCS, the RAMOT assay opens up new routes in label-free image-based drug discovery. 5:05-5:30 Image Analysis and Modeling of Cardiomyocyte Hypertrophy Jeffrey Saucerman, Ph.D., Assistant Professor, Biomedical Engineering, University of Virginia Cardiomyocyte hypertrophy plays a key role in the transition to heart failure. We are developing automated microscopy and image analyses to quantify the hypertrophy dynamics of individual live primary cardiomyocytes. I will present two applications. In the first, we characterized the kinetics of myocyte hypertrophy in response to transient receptor agonists. In the second example we used automated imaging to validate model predictions about the quantitative role of 11 parallel hypertrophy pathways. 5:30-5:55 An Evolving View of Cancer: High-Content Analysis and Mathematical Modeling to Study Cancer Cell Heterogeneity and Resistance Arijit Chakravarty, Ph.D., Senior Scientist, Modeling and Simulation, DMPK, Millenium Pharmaceuticals The changing picture of the landscape of carcinogenesis and tumor response to therapy frames cancer as a disease of genomic instability and somatic Darwinian evolution. Developing realistic model systems and methodologies to study heterogeneity and evolution in populations of cancer cells would be the first step in leveraging the emerging picture of cancer in oncology drug development. In this presentation I will discuss the challenges posed by tumor heterogeneity and evolution, and the methods by which high-content analysis techniques, coupled with mathematical modeling, allow us to study this process. 6:00-7:00 Networking Reception in the Exhibit Hall with Poster Viewing Sponsored by Phenotypic Drug Discovery 6 | High-Content Analysis HighContentAnalysis.com
Cambridge Healthtech Institute’s TENTH Annual January 8-11, 2013 High-Content Analysis Anniversary Thursday, January 10, 2013 7:30-8:15 am Breakfast Presentation Sponsored by Spots to Spheres: Parasites to 3-D Cancer Models for Drug Discovery Vicky M. Avery, Ph.D., Professor, Chief Investigator and Head, Discovery Biology (Avery Lab), Eskitis Institute for Cell & Molecular Therapies, Griffith University The focus of our laboratory is drug discovery and how we can improve the process, or obtain more information from the data we generate. This presentation will provide exemplars of the image-based assays utilized to identify new small molecule inhibitors and modulators of parasitic diseases and cancer, as well as those used to investigate the mechanisms involved. 8:15-8:25 Award Presentations Cellume Award Poster Competition GE Image Competition Sponsored by Sponsored by 8:25-8:30 Chairperson’s Opening Remarks 8:30-8:55 The Value of Phenotypic Assays to Drug Discovery David C. Swinney, Ph.D., CEO, Institute for Rare and Neglected Diseases Drug Discovery (iRND3) Drug discovery strategies include target-based molecular approaches and phenotypic-based empirical approaches. Our recent analysis revealed the phenotypic approach as the more successful strategy for first-in-class medicines. We rationalized that this success was influenced by the unbiased identification of a molecular mechanism of action (MMOA) that contributed to a useful therapeutic index. The value and success of phenotypic approaches will be further increased through efforts to bridge the gap between molecular approaches and phenotypic approaches such that once an effective MMOA has been confirmed with phenotypic assays, molecular approaches can be efficiently utilized to optimize leads to medicines. 8:55-9:20 Modern Phenotypic Drug Discovery Is a Viable Pharma Strategy Jonathan A. Lee, Ph.D., Senior Research Advisor, Quantitative Biology, Eli Lilly & Co. The majority of first-in-class NMEs originate from phenotypic screening (PS); however, this approach is not commonly used by the pharmaceutical industry. We addressed perceived issues with PS by conducting an antiangiogenesis MTS. Identification of novel chemical scaffolds that are differentiated, structurally and mechanistically, from anti-angiogenic standards of care and which modulate molecular targets not previously associated with angiogenesis demonstrates that PS interrogates relevant biology regardless of target validation status. Modern PS combines the biological complexity of physiology-based systems with the high-throughput compound testing capacity and operational robustness of biochemical methodologies. 9:20-9:45 High-Content Phenotypic Screening for Target Identification at Pfizer: High-Throughput Flow Cytometry and Live-Cell Imaging of Human Primary Cells Regis Doyonnas, Ph.D., Senior Principal Scientist, Stem Cell Engineering and High-Content Screening Lab, Hit Discovery and Lead Profiling, PDM-NCE, Worldwide Research & Development, Pfizer 9:45-10:45 Coffee Break in the Exhibit Hall Sponsored by with Poster Viewing 3-D Cell-Based Assays 8:25-8:30 Chairperson’s Opening Remarks 8:30-8:55 Overcoming the Challenges of Implementing 3-D Cell- Based Assays in Automated High-Content Screening Workflows Anthony M. Davies, Ph.D., Director, Irish National Center for High- Content Screening and Analysis (INCHA) To meet the needs of our in-house drug discovery and target identification programs, we have developed a novel 3-D cell culture system that has been specifically designed for use with HCS/A imaging and automated liquid handling. Unlike the 3-D assay systems currently used, our technology does not rely upon solid gel matrices, scaffolds, micropatterned surfaces or hanging drop assay systems to achieve reproducible cancer spheroid growth, hence offering advantages in flexibility and ease of use in an HCS/HTS environment. In this presentation we examine (i) Some of the most commonly used 3-D assay systems and their advantages and disadvantages when used in conjunction with HCA; (ii) In the same context we will also present our own 3-D cell suspension technology and the latest data derived from its use. 8:55-9:20 3-D Hepatocyte Culture to Profile Compounds Marc Bickle, Ph.D., Head, HT Technology Development Studio, Max Planck Institute of Molecular Cell Biology and Genetics 3-D cell culture increases the physiological relevance of cellular systems. In this context we have established a 3-D hepatocyte cell culture system, where polarized hepatocytes form bile canaliculi. In this system we have established assays to probe secretion, endocytosis, mitochondria, peroxisomes, autophagy and lipid droplets in order to profile compound action on these various cellular pathways. These assays will help predict the toxicity of compounds and establish their mode of action. 9:20-9:50 Sponsored Presentations (Opportunities available. Contact Katelin Fitzgerald at kfitzgerald@ healthtech.com or 781-972-5458.) 9:50-10:45 Coffee Break in the Exhibit Hall Sponsored by with Poster Viewing HighContentAnalysis.com High-Content Analysis | 7
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