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: Our interest in CF has shifted to the development of lung emphysema – the ultimate cause of death in the patient. In a truly translational collaboration with the Mall group (MMPU), we develop FRET reporters to sense enzyme activities detrimental to lung tissue, such as macrophage and neutrophil elastases. At the cell biology level, our interest focuses on signalling networks regulated by G-protein-coupled and growth factor receptors. We developed a wide range of fluorescent reporter molecules, either genetically encoded (Piljić & Schultz, 2011) or as small molecule fluorescent probes (see figure). We hope to provide a more complete picture of the signalling network and to help find compounds beneficial in unravelling basic principles in signal transduction and, ultimately, in ion and enzyme secretion relevant to CF patients or in insulin secretion of s-cells. In addition, we prepared a large number of tools to manipulate signalling networks and are able to locally activate the important messenger such as PIP3 and DAG with a light flash in subcellular resolution in living cells (Mentel et al. 2011; Nadler et al. 2013, Nadler et al. submitted). In order to specifically label molecules with fluorophores in intact cells, we prepare highly stable unnatural amino acids that rapidly and irreversibly undergo cycloaddition reactions (click chemistry) with unsurpassed speed and study their application in collaboration with the Lemke group.
Hot projects: Currently, we are very excited about making highly charged dyes pass cell membranes. In collaboration with the Häring group, we are developing a method to visualise protein-protein interactions in cells in real time. By using a novel set of photoactivatable lipid molecules, we are able to modulate the signalling underlying insulin secretion, likely to provide new means of identifying targets important in diabetes.
Future projects and goals
We will continue work aimed at bringing fluorescent reporters for enzyme activities closer to the clinic. We will also focus on lipid signalling and lipid-controlled cell biology, and examine the effect of sphingo- and phospholipids on endocytosis, lipid trafficking, and insulin secretion. In addition, we will improve our possibilities to fluorescently label molecules in intact cells by using faster and more complete bioorthogonal reactions and new fluorophores. Most projects rely on organic chemistry and the group has a significant number of preparative chemists at the graduate student and postdoc level. The symbiosis of chemistry, biochemistry, and cell biology opens new doors and grants novel insights into how cells exhibit their function.