Solute carrier (SLC) transporters are a large and diverse class of relatively understudied transmembrane proteins. Due to their critical role in cellular homeostasis, physiological processes and... Show moreSolute carrier (SLC) transporters are a large and diverse class of relatively understudied transmembrane proteins. Due to their critical role in cellular homeostasis, physiological processes and disease development, there is a great number of SLCs that have the potential to be viable drug targets for the treatment of disease. Robust assays are required to identify and characterize potential drugs for SLCs, which are often screened in vitro using cell-based or cell-free systems. Conventional assays either require the use of chemical labels, which i) can be invasive and compromise a cell’s physiology, ii) are based on end-point measurements, iii) use cell preparations and/or iv) do not allow screening of a large number of compounds. This thesis presents the development and application of novel label-free assays based on electrical impedance that allow the assessment of functional activity for three human SLCs: the dopamine transporter (DAT, SLC6A3), norepinephrine transporter (NET, SLC6A2) and excitatory amino acid transporters (EAAT, SLC1 family). With the ability to screen and characterize SLC inhibitors, these assays are a new addition to the ever-expanding toolbox for SLC transporters and could prove valuable in drug discovery programs for a wide range of diseases. Show less
This thesis describes various analyses of life science data with the aim of achieving efficiency gains in future experimental campaigns geared toward discovering drugs, and gaining novel... Show moreThis thesis describes various analyses of life science data with the aim of achieving efficiency gains in future experimental campaigns geared toward discovering drugs, and gaining novel insights into compound mode-of-action (i.e., the protein target modulated for the desired phenotypic effect). The increase in publicly available life science data has created opportunities for bioactivity modeling, and the role cheminformatics and bioinformatics play in the latter is discussed in detail. Show less
This thesis focuses on the development of image analysis methods for ultra-high content analysis of high-throughput screens where cellular phenotype responses to various genetic or chemical... Show moreThis thesis focuses on the development of image analysis methods for ultra-high content analysis of high-throughput screens where cellular phenotype responses to various genetic or chemical perturbations that are under investigation. Our primary goal is to deliver efficient and robust image analysis platforms which can 1) automatically detect cellular structures of interest from florescence microscope images and 2) quantify dynamics and organization of multi-cellular systems with phenotypic features. To recover heterogeneity of cellular behavior, we aim to develop single-cell-based image analysis methods so that cell subpopulations can be distinguished and investigated. Furthermore, we intend to develop methods to extract an ultra-high level of phenotypic details from images. This would enable system-level studies of phenotype characterization. Show less
