Research projects

Integrative structural biology of pathological tau protein, an appealing therapeutic target for Alzheimer’s disease modifying drugs (2020-2023)

There is an enormous unmet medical need to find efficient methods of prevention, diagnosis and disease-modifying therapies for tauopathies, including Alzheimer’s disease. The common molecular denominator of tauopathies are pathological forms of tau protein. Tau pathology relates to conformational changes during oligomerization and assembly resulting in toxicity. Given its role in the pathogenesis, conformationally altered and assembled tau would be a promising molecular target for disease-modifying therapy. However, the field is still lacking deeper understanding of tau structural changes in the course of assembly and their inducers on the pathway towards the pathological forms of Tau; therefore, pharmaceutical development is hampered. The main aim of the InterTau project is the detailed structural and biophysical characterization of tau protein and its variants in monomeric, oligomeric and fibril states relevant for AD and other tauopathies. The InterTAU consortium is composed of a clinical-stage biotech company pursuing development of anti-tau immunotherapy and academic partners with cutting-edge methodologies suitable for functional and structural characterization of tau assembly by solution and solid-state nuclear magnetic resonance (NMR), cryo-electron microscopy and cellular assays corroborated by bioinformatics. The mutual transfer of complementary expertise envisaged in the project will facilitate academic outcome and biotechnological development. Specific expertise will be transferred from three institutions in North America and one institution from Argentina. The results of InterTAU will be directly translated into innovation in pharmacological development through the non-academic partner. The platform for sharing knowledge will be a foundation of sustainable cooperation beyond the InterTau project.

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 873127 – InterTAU.

Novel 19F NMR based methods for structural biology of pathological tau protein, an appealing Alzheimer ́s disease therapeutic target (2020-2022)

Alzheimer’s disease and other tauopathies pose a formidable clinical challenge as well as several unmet medical needs to find efficient tools and therapies for their prevention, diagnosis and treatment. All tauopathies are associated with aggregation of pathological forms of the tau protein leading to neurofibrillary tangles in the brain, which makes it a promising target for therapy. However, there is still lack of understanding of the factors and conformational changes during tau oligomerization and assembly that result in specific pathologies. The proposed project aims to unravel the structural and dynamic details of the tau assembly pathway towards the pathological forms by establishing innovative approaches based on solution and solid-state nuclear magnetic resonance (NMR). We will build on cutting-edge methodologies and novel approaches for synthesis and incorporation of 19F labelled amino acids and high-sensitivity NMR experiments to obtain structural and functional characterization of the tau protein and its variants in monomeric, oligomeric and filamentous states relevant for disease. The project will heavily benefit from collaboration with partners of the H2020-MSCA-RISE InterTAU project. The project results will form the basis of innovation in the treatment of Alzheimer’s disease and other tauopathies.
Planned total implementation time of the project: 36 months.
Planned referable costs of the project are € 151 470.
The project is financed by the Latvian Council of Science.

Chemically modified artificial spider silk (2019-2022)

Spider silk is biocompatible, biodegradable, strong and elastic, which makes it ideal for biomedical applications. However, harvesting of silk from spiders is not feasible for large scale industrial purposes and current biotechnological approaches face problems with low recombinant protein yields as well as difficulties reproducing the native mechanisms of fibre spinning. The aim of the present project is to develop a novel method based on bioconjugation with polyethylene glycol for obtaining chemically modified artificial spider silk in a biomimetic way. The developed method would have several advantages in comparison to a purely biotechnological approach as it would ease recombinant spider silk protein (spidroin) expression in bacteria by circumventing the requirement for all three spidroin domains, allow crosslinking between spidroins as well as easy tuning of material properties by varying the bioconjugation reaction conditions. Successful implementation of the project will contribute to the development of several defined specialization areas of the Latvian Smart Specialization Strategy (RIS3) – biomedicine, medical technologies, biopharmacy and biotechnology. The project results will be applicable to development of new biomaterials with potentially broad applications in biomedicine and nanotechnology and thereby contribute to transformation of economy of Latvia towards high added value products.
To achieve the project objectives, an interdisciplinary study combining applied and basic research in the fields of chemical and biological sciences, and materials engineering (field classification codes 1.4, 1.6 and 2.5) will be carried out, particularly involving bioorganic chemistry, molecular and structural biology, biotechnology and materials science research. The project is unrelated to economic activities as it is implemented individually by a scientific institution, which carries out an independent study for obtaining more knowledge and better understanding (NACE code 72.19). The following activities will be performed within the framework of the project: 1) research for gaining new knowledge and developing a new technology; 2) dissemination of the research results, including publishing of 2 scientific articles, presentations at 9 conferences and informing of the project target group; 3) protection of intellectual property rights.
Planned total costs of the project are 561 334 euro. Place of implementation – Latvian Institute of Organic Synthesis (LIOS). Planned time period of project implementation is June 1st, 2019 to May 31st, 2022. The project is co-financed by the European Regional Development Fund.

From molecules to crystals: molecular self-assembly in crystal nucleation from solution (2018-2020)

Crystallisation is the most common method of chemical compound isolation from solution, and it is extensively used in chemical, food and pharmaceutical industry. Nevertheless, early stages of crystallisation are still poorly understood. Nucleation – the formation of the first stable embryonic structure of crystal in supersaturated solutions, plays a central role in determining the structure and size distribution of the final crystals, therefore, understanding the fundamental nucleation aspects are crucial to the control of crystallisation processes.
To advance our understanding of nucleation mechanism at a molecular scale, here we plan to investigate molecular association in the supersaturated solutions, rationalize the effect of the solvent and solute molecular structure and conformation on the nucleation pathway, and explore nucleation in systems in which changes in solvent change the polymorph obtained. A combination of thermodynamic, structural and modelling approaches will be used. This will include: investigation of solute molecule self-association in various solvents using NMR, FTIR and UV-Vis spectroscopies; probing supersaturated solutions for the presence of ordered precursors (using SAXS and WAXS); crystal nucleation kinetics measurements; and computational nucleation modelling. The organic compounds employed in this research will be of pharmaceutical and academic interest.
The project will be carried out in collaboration with Prof. A. S. Myerson research group at Massachusetts Institute of Technology and Dr. M. Salvalaglio research group at University College London.
Planned total implementation time of the project: 24 months.
Planned referable costs of the project are € 200 000.
The project is financed by the Latvian Council of Science.

Understanding prion peptide fibril-induced aggregation of prion protein (2017-2019)

Prion-like spreading may be employed in a number of fatal neurodegenerative disorders, including such as Alzheimer’s and Parkinson’s diseases. Understanding all possible mechanisms of such spreading would be a big step towards curing these diseases.
Recent work showed that prion protein aggregation can be induced by short peptides. It seems that either structure of peptide-induced prion protein aggregates (piPrP) or the mechanism of its formation is different from the current knowledge in the field.
We propose a comprehensive study of piPrP structure, starting from low resolution methods as Fourier transform infrared (FTIR) spectrometry and proteinase K (PK) resistance studies, but focusing on medium and high-resolution methods in hydrogen exchange mass spectrometry (HXMS), electron spin resonance spectrometry (ESR), and solid-state nuclear magnetic resonance spectroscopy (ssNMR). High resolution structure will lead to the ultimate goal of our research – getting deeper into mechanisms of prion-like self-replication of amyloid fibrils.
The project will be carried out in collaboration with Institute of Biological Chemistry, Academia Sinica, Taiwan and Vilnius University, Lithuania. Planned total implementation time of the project: 36 months. Total costs of the project are € 202 500, costs for Latvian partner € 67 500.
The project is financed by Mutual fund Taiwan – Latvia – Lithuania.

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