Figure 1: Several reporter and modulator molecules have been developed in our lab, including: small molecule sensors for lipases and proteases; genetically encoded reporters for kinase and phosphatase activities; membranepermeant and photoactivatable lipid molecules; and lipid derivatives that can be fluorescently labelled in living cells.
The Schultz group develops tools for imaging and for manipulating cellular enzyme activities, with a particular emphasis on lipid signalling in diabetes and the hereditary disease cystic fibrosis.
Previous and current research
Past projects: Our research has previously focused on finding novel ways to stimulate chloride and water secretion of epithelial cells in understanding cystic fibrosis (CF). Our compounds helped to investigate some of the underlying intracellular signalling pathways and provided drug candidates to eventually treat CF patients. Of particular significance was the development of chemical methods to convert highly polar signalling molecules like cyclic nucleotides, inositol phosphates, and phosphoinositides to membrane-permeant, bioactivatable derivatives (‘prodrugs’) (Schultz 2003; Laketa et al. 2009, Laketa et al. 2014).
Current projects: Generally, the Schultz group is interested in synthesizing and applying molecular tools to investigate disease-relevant signaling events and entire signaling networks. The goal is to visualize or manipulate key cellular parameters, ideally in living cells or organisms. Currently, this concept was applied to such diverse topics as i) the study of immune cell activity in cystic fibrosis and chronic obstructive pulmonary disease (COPD), ii) the development of ultra-fast clicking amino acids for in vivo protein labeling, iii) the synthesis of caged and photo-crosslinking lipids to elucidate the role of these under-appreciated signaling molecules, and iv) the generation and application of FRET-based sensors to monitor kinase, phosphatase, protease, and lipase activities and their use in live cell array techniques (Kuchenov et al., Cell Chem. Biol. 2016).
Future projects and goals
The Schultz lab is currently moving from the EMBL to Oregon Health & Science University in Portland, OR, USA. While most of the above mentioned topics will be continued, a strong new focus will be laid on the signaling network instrumental in driving insulin secretion in ß-cells and applications of our tools in neurobiology and neuroendocrinology at the physiological level. Explicitly, we are currently investigating the extracellular signaling network in islets of Langerhans (Frank et al., Chem. Sci. 2017; Schifferer et al., Cell Chem. Biol. 2017; Hauke et al., Diabetes 2018), the role of phosphoinositides in intracellular trafficking in collaboration with Volker Haucke in Berlin (Ketel et al., Nature 2016; Marat et al., Science 2017) and the development and use of photo-crosslinking tools to study lipid-protein and protein-protein interactions (Höglinger et al., PNAS 2017; Hoffmann et al., Biochemistry 2018). These projects will be propelled into a more physiological context with experiments in intact organisms.