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Research project (§ 26 & § 27)
Duration : 2022-06-01 - 2025-11-30

C-type lectin-like receptor 2 (CLEC-2) is involved in two important processes of platelet biology: separation of blood and lymphatic vessels and thrombosis. Besides being considered a potential drug target in settings of wound healing, inflammation, infection, and cancer, CLEC-2 is gaining interest as a therapeutic target for a variety of thrombo-inflammatory disorders with treatment also predicted to cause minimal disruption to hemostasis. While the last few years have seen major advances in our understanding of CLEC-2 ligand interactions and the resulting signaling cascades, the mechanisms by which the different biological functions are controlled are still insufficiently understood. Elucidation of these pathways is bottlenecked by a lack of chemical tools to investigate and visualize the effects of receptor multimerization on signaling and ligand fate. This project aims at establishing a platelet-specific liposomal platform for mechanistic and targeted-delivery studies. Liposomal nanoparticles are decorated with natural as well as newly developed high-affinity ligands of CLEC-2 prepared by chemical synthesis. The opportunity to control ligand affinity and density on the nanoparticles will enable detailed studies into CLEC-2 biology and thus exploration of CLEC-2 as a therapeutic target for small-molecule inhibitors and for delivery devices for nucleic acids and other drugs.
Research project (§ 26 & § 27)
Duration : 2022-06-01 - 2025-05-31

Wider research context: The demand of current societies, with ever-increasing populations, for food, energy, and materials grows dramatically, resulting in a clear need for increased crop productivity. Crop improvement for food, fiber, and biofuels production will greatly benefit from a more detailed understanding of plant immune function. Plants sense and respond to pathogen attacks by using an arm of the plant immune system that relies on the detection of exogeneous Microbe-Associated Molecular Patterns (MAMPs) and endogenous Danger-Associated Molecular Patterns (DAMPs) by Pattern-Recognition-Receptors (PRRs), such as Receptor-Like-Kinases (RLKs). Despite the large number of RLKs in plants and the dominating presence of glycans in the cell walls of plants, bacteria, and fungi, only a handful of glycans were found to elicit plant immune responses, and only for two of those the cognate receptors have been described. We recently identified two novel glycan-RLK pairs by interrogating glycan arrays with heterologously expressed extracellular RLK domains and further confirmed the immune activities of these glycans in vivo. Objectives: We aim at establishing the plant polysaccharides rhamnogalacturonan-I (RG-I) and galactomannan (GM) as novel DAMPs for activation of plant innate immunity as well as determining the exact molecular patterns recognized by their cognate RLKs. Approach: Chemical synthesis of collections of RG-I and GM oligosaccharides will enable the glycan array-based characterization of recently discovered RG-I- and GM-binding RLKs. After hit validation in further biophysical assays, the identified oligosaccharides will be investigated in vivo towards their potential to stimulate ROS-production, MAP-kinase activation, and defense genes induction as hallmarks of immune activation. Innovation: The unique approach to combine synthetic carbohydrate chemistry and glycan arrays with plant immunity research will enable the elucidation of refined molecular structures with maximum capacity to elicit immune responses. The generated knowledge will facilitate the development of preparations of glycan molecules to boost the plant immune system, avoiding the need for using traditional pesticides.
Research project (§ 26 & § 27)
Duration : 2022-04-01 - 2025-03-31

Wider research context: Plant cell walls provide the richest available resource of fermentable carbohydrates and bio-based materials. Optimal exploitation of this resource requires an in-depth knowledge of the molecular structure and biosynthesis of plant cell wall glycans. Besides cellulose, which is constructed from relatively simple -1,4-glucan chains, plant cell walls also contain the structurally more complex heteropolysaccharides hemicelluloses and pectin as well as lignin and cell wall proteins. The most complex cell wall glycan is rhamnogalacturonan-II (RG-II), a highly conserved low-molecular-weight pectic polysaccharide, containing twelve different types of monosaccharides that are connected through 20 different linkages. Pure oligosaccharide samples that represent structural features of complex cell wall glycans such as RG-II are powerful molecular tools for various biochemical assays and indispensable for continuous progress in plant cell wall research, but are of limited availability. Objectives: We will develop synthetic strategies to access oligosaccharide fragments of RG-II, which will be employed in glycan array assays aiming at the identification and characterization of RG-II-specific antibodies and RG-II-biosynthetic enzymes. Approach: The complex structure of RG-II poses enormous challenges for organic chemists: 1) The rare monosaccharides apiose and aceric acid need to be synthesized de novo and converted into suitable glycosyl donors. 2) The high number of uronic acid residues mandates a post-assembly-oxidation strategy. 3) The highly branched, congested structure of RG-II complicates the design of a suitable convergent synthetic strategy. 4) A large number of 1,2-cis-glycosidic bonds must be prepared in a stereoselective manner using individually optimized glycosylation protocols. Through utilization and further development of the most recent methodologies in synthetic carbohydrate chemistry these challenges will be met, and a collection of complex RG-II fragments up to the size of decasaccharides will be prepared. The prepared oligosaccharides will be printed as glycan arrays and screened with pectin-directed antibodies as well as putative glycosyltransferases (GTs) responsible for RG-II biosynthesis. Innovation: The availability of highly complex RG-II fragments will for the first time enable the systematic elucidation of RG-II biosynthesis and the detection and monitoring of specific RG-II epitopes within plant cell walls using fluorescence microscopy. The generated knowledge will facilitate future developments towards improved biomass digestibility, material strength of plant-derived products, and the shelf life of fruits and vegetables.

Supervised Theses and Dissertations