Division of Gene Technology and Biomedicine | Department of Chemistry and Biotechnology

We research and develop highly automated technologies and instrumentation for Lab-on-a-Chip applications. Our focus is on applying industry 4.0 to solving problems in Lab-on-a-Chip: machine learning to discern biological objects, wireless communication between bioanalytical devices, digital manufacturing of instrumentation etc. Our goal is to deliver technologies that are user-friendly and open to everyone.

People

Group Leader - Dr. Tamas Pardy (tamas.pardy@taltech.ee),
Professor emeritus Toomas Rang,
Nafisat Gyimah,
Rauno Jõemaa

https://orcid.org/0000-0003-1360-4201

The main topic of our research group is related to the identification of fundamental aspects of lipid and lipoprotein metabolism. Lipid and lipoprotein metabolism is associated with several health conditions, such as hypertriglyceridemia, cardiovascular diseases, pancreatitis, obesity and diabetes. Our main focus is studying the regulatory mechanisms of key enzymes (lipases) involved in lipid and lipoprotein metabolism. We have competence and experience in the study of the structure and properties of proteins, in enzymology  and in the analysis of biomolecular interactions, as well as lipid analysis. In our research, we mainly apply calorimetry, chromatography, mass spectrometry, surface plasmon resonance and fluorescence-based technologies. Our work has led to industrial collaborations with companies such as Opocrin SPA (Italy) and Lipigon Pharmaceuticals (Sweden).

MAIN RESEARCH TOPICS INCLUDE:

• Studying the regulatory mechanisms of lipoprotein lipase activity
• Determining lipoprotein lipase activity in different human plasma environments
• Further development in pancreatic lipase and gastric lipase activity assays
• Development of an anti-hypertriglyceridemic drug formulation based on recombinant human lipoprotein lipase

MEMBERS OF THE RESEARCH GROUP:

Group leader: Aivar Lõokene
Group members: Robert Risti, Ly Villo, Ivar Järving
PhD students: Naatan Seeba
MSc students: Liise Hämarmets
Post Docs: Mart Reimund

Patents: Method for calorimetric determination of the lipoprotein lipase activity in human plasma environment https://www.etis.ee/Portal/IndustrialProperties/Display/03b7bf76-e353-4b1c-8746-9e1100b2c51f

CONTACT INFORMATION:

Aivar Lõokene, lead research scientist, head of the lipid and lipoprotein metabolism lab
E-mail: aivar.lookene@taltech.ee
Address: Building of Science, Akadeemia road 15, room 320
CV: https://www.etis.ee/CV/Aivar_L%C3%B5okene/eng/

• Combined action of albumin and heparin regulates lipoprotein lipase oligomerization, stability, and ligand interactions: https://doi.org/10.1371/journal.pone.0283358
• Lipoprotein Lipase Activity Does Not Differ in the Serum Environment of Vegans and Omnivores: https://doi.org/10.3390/nu15122755
• Leptin increases hepatic triglyceride export via a vagal mechanism in humans: https://doi.org/10.1016/j.cmet.2022.09.020
• Calorimetric approach for comparison of Angiopoietin-like protein 4 with other pancreatic lipase inhibitors: https://doi.org/10.1016/j.bbalip.2019.158553
• Apolipoprotein C-II mimetic peptide is an efficient activator of lipoprotein lipase in human plasma as studied by a calorimetric approach: https://doi.org/10.1016/j.bbrc.2019.08.130
• Lipoprotein lipase activity and interactions studied in human plasma by isothermal titration calorimetry: https://doi.org/10.1194/jlr.D071787
• Evidence for Two Distinct Binding Sites for Lipoprotein Lipase on Glycosylphosphatidylinositol-anchored High Density Lipoprotein-binding Protein 1 (GPIHBP1): https://doi.org/10.1074/jbc.M114.634626

Cellular, Extracellular and Extracellular Vesicular miRNA Profiles of Pre-Ovulatory Follicles Indicate Signaling Disturbances in Polycystic Ovaries || INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2020)
https://www.mdpi.com/1422-0067/21/24/9550

ELIMÄKI Locus Is Required for Vertical Proprioceptive Response in Birch Trees || CURRENT BIOLOGY (2020)
https://www.sciencedirect.com/science/article/pii/S0960982219316112 

Molecular profile of the rat peri-infarct region four days after stroke: study with MANF || EXPERIMENTAL NEUROLOGY (2020)
https://www.sciencedirect.com/science/article/pii/S0014488620301199 

Droplet-based digital antibiotic susceptibility screen reveals single-cell clonal heteroresistance in an isogenic bacterial population || SCIENTIFIC REPORTS (2020)
https://www.nature.com/articles/s41598-020-60381-z 

Evolutionary Origin of the P2X7 C-ter Region: Capture of an Ancient Ballast Domain by a P2X4-Like Gene in Ancient Jawed Vertebrates || FRONTIERS IN IMMUNOLOGY (2020)
https://www.frontiersin.org/articles/10.3389/fimmu.2020.00113/full?report=reader 

Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium || NATURE (2019)
https://www.nature.com/articles/s41586-019-1383-0 

Biomedicine lab investigates Helicobacter pylori (HP) and its role in the development of liver diseases. HP is a Gram-negative bacterium living in the hostile environment of the human stomach. About 70% of the adult population in Estonia is infected with HP. The bacterium causes gastritis and peptic ulcers, and, in some cases, gastric cancer. HP can also affect other organs including the liver.

Main research topics include:

•    Role of Helicobacter pylori-induced invadosomes in liver damages. We have previously shown that infection with HP induces the formation of invadosomes in hepatocytes. We are currently investigating the mechanism behind this phenomenon using in vitro approach complemented with transcriptome sequencing.
•    Clinical aspects of Helicobacter pylori-induced liver diseases. We are using the livers of mice infected with HP to analyse short- and long-term effects of the infection with focus on different markers such as YAP1 and CD44.
•    Alteration of gut microbiota by Helicobacter pylori leading to the progression of liver diseases. For this study, we are collecting samples from Estonian patients. Our goal is to characterize Estonian HP strains, their effect on mouth/stomach/gut microbiota and liver.

Members of the research group

Group leader: Pirjo Spuul
PhD students: Olga Smirnova, Kaisa Roots, Sadia Khalid
MSc students: Liisa Truu, Lilian Ventsel, Stella Marleen Hõlpus

Contact information

Pirjo Spuul, senior researcher, head of the biomedicine lab
E-mail: pirjo.spuul@taltech.ee
Address: Building of Science, Akadeemia road 15, room 140
CV: https://www.etis.ee/CV/PirjoSpuul/est?tabId=CV_ENG

Varon, C. et al., (2021). Seminars in Cancer Biology, S1044-579X(21)00219-4. DOI: 10.1016/j.semcancer.2021.08.007

Durán, C. et al., (2021). Nature Communications, 12 (1), #1926. DOI: 10.1038/s41467-021-22135-x

Le Roux-Goglin, E. et al., (2012). European Journal of Cell Biology, 91 (3), 161−170. DOI: 10.1016/j.ejcb.2011.11.003

Link to publications

PI: Sirje Rüütel Boudinot, docent, senior researcher Tallinn University of Technology
Department of Chemistry and Biotechnology 
Academical members:
PhD students: Airi Rump, Kadri Orro, Roland Martin Teras
Researcher: Viiu Paalme
Non-academical members: Emilia Di Giovanni (Erasmus student from University of Palermo)

Key words: immunregulation, leukocyte activation, RGS16, P2X4, P2X7, Multiple Sclerosis, melanoma, eosinophils, Covid19

Fields of research: Biological Sciences, Medical and health sciences.

Description of the project: 
The Immunology group at TTU focuses on the biology of leukocyte activation and its regulation. The control of leukocyte activation is of paramount importance for health, both at steady state and during the immune response, to warrant the resilience of the immune system. Dysfunctions of these critical mechanisms lead to auto-inflammatory and auto-immune diseases and also strongly affect the efficiency of defence against pathogens.
We selected two families of regulators of which functions remain poorly understood, the RGS (Regulator of G protein Signalling; main gene target rgs16) and the purinergic receptors (P2X main targets p2x4 and p2x7). We studied control mechanisms of leukocyte activation mediated by these genes in the context of two pathologies: multiple sclerosis and melanoma. Using a combination of in vitro and in vivo (KO mice) models, we performed gain and loss of function experiments to characterize regulatory mechanisms mediated by our genes of interest. We will also determine how modulating P2X4 receptor activity could development of pro- versus anti-inflammatory phenotype of leukocytes  (especially in eosinophils) during viral infection and cancer models. We also followed comparative approaches to understand the importance of these genes in the context of the evolution of the immune system. 

Main results in 2021:
We have previously identified that RGS16 is involved in the type I IFN response to viral infections and showed that RGS16 mediates the production of multiple pro inflammatory cytokines in monocytes [Suurväli et al 2015]. Using a RGS16 KO mouse we were able to show that disruption of rgs16 confers an acute sensitivity to LPS, and exacerbate Experimental Autoimmune Encephalomyelitis (EAE), a model of multiple sclerosis (Siimut master thesis, Aitai master thesis, manuscript in preparation Rump et al 2022). We also showed in RGS16 KO mice that the expression of RGS16 by recipient mice inhibited the development of grafted melanoma in vivo. (Teras  et al 2018 a]. However, this mechanism was not required for the antitumoral effect of the apoptin protein (ORF3) of the circovirus PCV2, which was based on the induction of apoptosis [Teras  et al 2018 b].  In collaboration with PERH we demonstrated an effective melanoma treatment method  (Teras et al 2020; and PhD thesis Marina Teras, collaboration with PERH). 

Among purinergic receptors, P2X7 is by far the best-known effector of activation during immune responses.  We showed that P2X7 receptor resulted from the fusion of a P2X4 similar gene with an exon encoding a ballast domain. (Rump et al, 2020a). We focused on P2X4, a purinergic receptor mainly studied in the nervous system, because its implication in the microglial reaction, and its potential involvement in multiple sclerosis, suggested it could also be important in immunity.  We wrote a reviewe where we describe diseases whose physiopathology involves P2X4 receptor signaling and summarize that signalling via P2X4 is highly pH dependent (Kanellopoulos et al 2021). We have now demonstrated that P2X4 is expressed by several leukocyte cell subsets. Strikingly, we identified eosinophils from human PBL as the population expressing the highest level of P2X4. As a new surface marker of human eosinophils, P2X4 appears as a useful target to get insight into their biology (Paalme et al 2019).
We demonstrated that the glycosylation of SARS-CoV-2-NP masks some of its antibody epitopes. In many cases, this can lead to false-negative serological tests. Deglycosylation of SARS-CoV-2-NP increased significantly the number of positive tests (Rump et al 2020b).

Future projects: 
We plan to characterize the role of P2X4 in the ATP-mediated activation of eosinophils (also mast cells and basophils), using the tools we have developed in collaboration with Professor Jean Kanellopoulos (University Paris Saclay, France). The genetic diversity of P2X4 in the estonian population, and its functional implications, will be addressed in collaboration with the Estonian genome project (PhD project of Airi Rump, co-supervised with O-P Smolander).  We also plan to validate  P2X4 receptor as a new marker of eosinophils and explore its relevance for prognosis of COVID severity and evolution.
 

Sirje Rüütel Boudinot, Associate Professor          
Molecular Immunology
Tallinn University of Technology
Department of Chemistry and Biotechnology 
Sirje.boudinot@gmail.com
+372 53099557

J. Suurvali, M. Pahtma, R. Saar, V. Paalme, A. Nutt, T. Tiivel, M. Saaremae, C. Fitting, J.M. Cavaillon, and S. Ruutel Boudinot, RGS16 restricts the pro-inflammatory response of monocytes. Scand J Immunol 81 (2015) 23-30.

M. Teras, E. Viisileht, M. Pahtma-Hall, A. Rump, V. Paalme, P. Pata, I. Pata, C. Langevin, and S. Ruutel Boudinot, Porcine circovirus type 2 ORF3 protein induces apoptosis in melanoma cells. BMC Cancer 18 (2018a) 1237.

Teras M, Rump A, Paalme V, Rüütel Boudinot S: Porcine Circovirus Type2      ORF3 protein            induces apoptoses in melanoma cells (abstract 2018- No  P.B1.03.15; Page 221; A-1919-ECI) Amsterdam, (2018b):       https://www.eci2018.org/fileadmin/user_upload/documents/ECI_2018_Abstra            ct_Book_web_21082018.pdf

Paalme, V.; Rump, A.; Mädo, K.; Teras, M.; Truumees, B.; Aitai, H.; Ratas, K.; Bourge, M.; Chiang, C.-S.; Ghalali, A.; Tordjmann, T.; Teras, J.; Boudinot, P.; Kanellopoulos, J.; Rüütel Boudinot, S. (2019). Human peripheral blood eosinophils express high level of the purinergic receptor P2X4. Frontiers in Immunology.10.3389/fimmu.2019.02074

Rump, A.; Smolander, O.-P.; Rüütel Boudinot, S.; Kanellopoulos, J. M; Boudinot, P. (2020).  Evolutionary origin of the P2X7 C-ter region: capture of an ancient ballast domain by a P2X4-like gene in ancient jawed vertebrates. Frontiers in Immunology, 11, 113−113. DOI: 10.3389/fimmu.2020a.00113. 

Teras, J.; Kroon, H. M.; Thompson, J. F.; Teras, M.; Pata, P.; Mägi, A.; Teras, R. M.; Rüütel Boudinot, S. (2020). First Eastern European Experience of Isolated Limb Infusion for In-Transit Metastatic Melanoma Confined to the Limb: Is it still an Effective Treatment Option in the Modern Era? European Journal of Surgical Oncology.  Vol 46, Feb 2020, p272-276. 

Rump, A.; Risti, R.; Kristal M.-L.; Reut, J.; Syritski, V.; Lõokene, A., Rüütel Boudinot, S. (2021). Dual ELISA using SARS-CoV-2 N protein produced in E. coli and CHO cells reveals epitope masking by N-glycosylation. Biochemical and Biophysical Research Communications, 534, 457−460. DOI: 10.1016/j.bbrc.2020b.11.060

Kanellopoulos J, Almeida-da-Silva CLC, Rüütel Boudinot S and Ojcius DM (2021) Structural and Functional Features of the P2X4 Receptor: An Immunological Perspective. Front. Immunol. 12:645834. doi: 10.3389/fimmu.2021.645834

Professor Peep Palumaa's research group is focused on the studies of the biological role and the regulation of two important transition metals - copper and zinc. Copper is an essential cofactor for more than twenty enzymes crucial for cellular energy production, antioxidative defense, and oxidative metabolism. Zinc is involved in cell metabolism and regulates gene expression as it is a cofactor for more than 200 enzymes and is involved in the structuring of more than 600 transcription factors (zinc finger proteins). Dysregulation of copper and zinc homeostasis occurs in multiple diseases, including Wilson's, Menkes, and Alzheimer's disease.

Metalloproteomics group has been studying copper and zinc metabolism through structural and functional studies of key metalloproteins for a long time. In addition, in the last years, they have been using also different cellular and insect models for researching copper and zinc involvement in Alzheimer's disease, such as cell culture and fruit flies. The expected results will substantially advance the knowledge on copper and zinc metabolism, and facilitate the search for molecular tools for its regulation. This is essential for understanding the cause of Alzheimer's disease and elaboration of an effective strategy for its treatment. The research group has different methods at their disposal - LC-ICP MS for ultrasensitive detection of metals, MALDI MS, spectrofluorometer, FPLC, HPLC, and UHPLC chromatographic systems for working with proteins, etc.

The head of the research group Prof. Peep Palumaa received the Estonian National Research Prize in Chemistry and Molecular Biology in 2011 and the TalTech Best Researcher Prize in 2012. Our students have frequently won prizes for their thesis and publications at competitions for student research organized by Estonian Ministry of Education and Research and by research societies.

The research group expects both master's and bachelor's students to conduct research and write their thesis. Please contact peep.palumaa@taltech.ee .

Peep Palumaa, Tenured Full Professor
Vello Tõugu, Associated Professor
Julia Smirnova, Research Scientist
Andra Noormägi, Engineer
Merlin Sardis, Engineer
Katrina Laks, Engineer
Julia Gavrilova, Engineer
Kristel Metsla, PhD student
Sigrid Kirss, PhD student
Jekaterina Kabin, PhD student

Kirsipuu, T.; Zadorožnaja, A.; Smirnova, J.; Friedemann, M.; Plitz, T.; Tõugu, V.; Palumaa, P. (2020). Copper(II)-binding equilibria in human blood. Scientific Reports, 10 (1), #5686. DOI: 10.1038/s41598-020-62560-4.

Krištal, J.; Metsla, K.; Bragina, O.; Tõugu, V.; Palumaa, P. (2019). Toxicity of Amyloid-β Peptides Varies Depending on Differentiation Route of SH-SY5Y Cells. Journal of Alzheimer's Disease, 879−887. DOI: 10.3233/JAD-190705.

Wallin, C.; Friedemann, M.; Sholts, S. B; Noormägi, A.; Svantesson, T.; Jarvet, J.; Roos, P. M.; Palumaa, P.; Gräslund, A.; Wärmländer, S. K. T. S. (2019). Mercury and Alzheimer's disease: Hg(II) ions display specific binding to the amyloid-β peptide and hinder its fibrillization. Biomolecules, 10 (1), 1−23. DOI: 10.3390/biom10010044.

Smirnova, J.; Kabin, E.; Järving, I.; Bragina, O.; Tõugu, V.; Plitz, T.; Palumaa, P. (2018). Copper(I)-binding properties of de-coppering drugs for the treatment of Wilson disease. α-Lipoic acid as a potential anti-copper agent. Scientific Reports, 8 (1, 1463), 1−9. DOI: 10.1038/s41598-018-19873-2.

Krishtal, J.; Bragina, O.; Metsla, K.; Palumaa, P.; Tõugu, V. (2017). In situ fibrillizing Amyloid-beta 1-42 Induce Neurite Degeneration and Apoptosis of Differentiated SH-SY5Y Cells. PLoS ONE. DOI: 10.1371/journal.pone.0186636.

Brancaccio, D.; Gallo, A.; Mikolajczyk, M.; Zovo, K.; Palumaa, P.; Novellino, E.; Piccioli, M.; Ciofi-Baffoni, S.; Banci, L. (2014). Formation of [4Fe-4S] clusters in the mitochondrial iron-sulfur cluster assembly machinery. Journal of the American Chemical Society, 136, 16240−16250.

Palumaa, P. (2013). Copper chaperones. The concept of conformational control in the metabolism of copper. FEBS Letters, 587 (13), 1902−1910.

Tiiman, Ann; Palumaa, Peep; Tõugu, Vello (2013). The Missing Link in the Amyloid Cascade of Alzheimer's Disease - Metal Ions. Neurochemistry International, 62 (4), 367−378.

Banci, L.; Bertini, I.; Cantini, F.; Kozyreva, T.; Massagni, C.; Palumaa, P.; Rubino, JT.; Zovo, K. (2012). Human superoxide dismutase 1 (hSOD1) maturation through interaction with human copper chaperone for SOD1 (hCCS). Proceedings of the National Academy of Sciences of the United States of America, 109 (34), 13555−13560.

Tõugu, V.; Palumaa, P. (2012). Coordination of zinc ions to the key proteins of neurodegenerative diseases: amyloid-β peptide, APP, α-synuclein and prion protein. Coordination Chemistry Reviews, 256, 2219−2224.

Tõugu, Vello; Tiiman, Ann; Palumaa, Peep (2011). Interactions of Zn(II) and Cu(II) ions with Alzheimer’s amyloid-beta peptide. Metal ion binding, contribution to fibrillization and toxicity. Metallomics, 3, 250−261.10.1039/c0mt00073f.

Zovo, Kairit; Helk, Eneken; Karafin, Ann; Tõugu, Vello; Palumaa, Peep (2010). Label-Free High-Throughput Screening Assay for Inhibitors of Alzheimer’s Amyloid-β Peptide Aggregation Based on MALDI MS. Analytical Chemistry, 82 (20), 8558−8565. DOI: 10.1021/ac101583q.

Banci, L.; Bertini, I.; Ciofi-Baffoni, S.; Kozyreva, T.; Zovo, K.; Palumaa, P. (2010). Affinity gradients drive copper to cellular destinations. Nature, 465 (7298), 645−648. DOI: 10.1038/nature09018.

Microfluidics is all about conducting biotechnological laboratory experiments in tiny channels and in small reaction volumes. It brings miniaturization and automation to biological and chemical applications. Microfluidic technologies can be applied to many different fields: medical diagnostics, basic molecular biology research, drug research, analytical chemistry, and many other areas.

Group website

We host ERASMUS exchange projects, also help to develop novel international PhD and postdoc projects. Interested people should contact the group leader Prof. Ott Scheler.

Current research topics:

• Droplets for high-throughput assays: In here we apply small (pL-nL sized) water-in-oil droplets that act as tiny test tubes, for microbiology and cell biology studies. We generate droplets with microfluidic or traditional emulsion generation tools. Typical droplet experiment can involve generating and analyzing hundreds of thousands (or even millions) of droplets. This enables carrying out single cell growth analysis studies in large scale.
  • We apply droplet technologies to study different microbiology related fields: i) antimicrobial resistance mechanisms, ii) microplastic and metal contamination, iii) biofilm formation, iv) microalgae for toxicology studies.
  • We also develop image analysis tools for droplet microfluidic research
• Automation for laboratory research: in this topic we develop devices for microfluidic and laboratory automation purposes. We do this in collaboration with Lab-on-a-Chip group led by Dr. Tamas Pardy.

Group members

Staff: Prof. Ott Scheler, Dr. Simona Bartkova, Dr. Immanuel Sanka, Pille Pata
PhD Students: Veiko Rütter (ICT PhD Student co-supervised with Dr. Tamas Pardy)
MSc students: Allar Lillepruun, Saari Anete Loog, Merili Saar, Mai-Ly Kristal (Main supervisor Dr. Agne Velthut-Meikas)
BSc students: Karoline Lindpere, Triini Olman, Ats Oskar Laansalu, Eva Katarina Tambets (Main supervisor Dr. Agne Velthut-Meikas)

ALUMNI AND VISITORS

Fenella Lucia Sulp   MSc 2023, BSc 2021
Katri Rüüson   Gymnasium project 2023
Immanuel Sanka   PhD 2023
Maryna Lazouskaya   PhD 2023
Justyna Gruszka    Erasmus+ staff exchange 2022
Katri Kiir    BSc 2022
Julia Vetik    MSc 2022
Monika Meinberg    Gymnasium project 2022
Sophie Carpin    Erasmus+ student 2021
Natali Agu    Gymnasium project 2021
Adam Opalski    Erasmus+ staff exchange 2019
Aap Muromägi    Gymnasium project 2020
Toomas Teekivi    BSc 2019

https://scholar.google.com/citations?hl=en&user=hi85YY4AAAAJ&view_op=list_works

Publications of the last 10 years
2021 eLife 
Tuvikene J., Esvald E.E., Rähni A., Uustalu K., Zhuravskaya A., Avarlaid A., Makeyev E. V.  Timmusk T. Intronic enhancer region governs transcript-specific BDNF expression in neurons. eLife, 2021, 10:e65161.

https://elifesciences.org/articles/65161

2020 Disease Models and Mechanisms 
Tamberg L., Jaago M., Säälik K., Sirp A., Tuvikene J., Shubina A., Kiir C. S., Nurm K., Sepp M., Timmusk T., Palgi M. Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome. Dis Model Mech, 2020, Dis Model Mech, 2020, 13: dmm042747.

https://journals.biologists.com/dmm/article/13/7/dmm042747/225154/Daughterless-the-Drosophila-orthologue-of-TCF4-is

2020 Journal of Neuroscience
Esvald, E. E.; Tuvikene, J.; Sirp, A.; Patil, S.; Bramham, C. R.; Timmusk, T. CREB Family Transcription Factors Are Major Mediators of BDNF Transcriptional Autoregulation in Cortical Neurons. Journal of Neuroscience, 2020, 40,1405-1426. 

https://www.jneurosci.org/content/40/7/1405

2018 Glia 
Koppel I., Jaanson K., Klasche A., Tuvikene J., Tiirik T., Pärn A., Timmusk T. Dopamine cross-reacts with adrenoreceptors in cortical astrocytes to induce BDNF expression, CREB signaling and morphological transformation. Glia, 2018, 66, 206-216.

https://onlinelibrary.wiley.com/doi/full/10.1002/glia.23238 

2017 Journal of Neuroscience
Sepp M., Vihma H., Nurm K., Urb, M., Page S. C., Roots K., Hark A., Maher B. J., Pruunsild, P., Timmusk T. The intellectual disability and schizophrenia associated transcription factor TCF4 is regulated by neuronal activity and protein kinase A. Journal of Neuroscience, 2017, 37, 10516-10527.

https://www.jneurosci.org/content/37/43/10516 

2016 Journal of Neuroscience
Tuvikene J., Pruunsild P., Orav E., Esvald E.E., Timmusk T. AP-1 transcription factors mediate BDNF-positive feedback loop in cortical neurons. Journal of Neuroscience, 2016, 36, 1290-1305. 

https://www.jneurosci.org/content/36/4/1290 

2016 Journal of Neurochemistry 
Vihma H., Luhakooder M., Pruunsild P., Timmusk T. Regulation of different human NFAT isoforms by neuronal activity. Journal of Neurochemistry, 2016, 137, 394-408. 

https://onlinelibrary.wiley.com/doi/full/10.1111/jnc.13568
 
2016 European Journal Medicinal Chemistry
Tammiku-Taul J., Park R., Jaanson K., Luberg K., Dobchev D. A., Kananovich D., Noole A., Mandel M., Kaasik A., Lopp M., Timmusk T., Karelson M. Indole-like Trk receptor antagonists. European Journal Medicinal Chemistry, 2016, 121, 541-552.

https://www.sciencedirect.com/science/article/pii/S0223523416304809 

2015 Biology Open 
Tamberg L, Sepp M, Timmusk T., Palgi M. Introducing Pitt-Hopkins syndrome-associated mutations of TCF4 to Drosophila daughterless. Biol. Open, 2015, 4, 1762-1771.

https://journals.biologists.com/bio/article/4/12/1762/1373/Introducing-Pitt-Hopkins-syndrome-associated

2015 Journal of Neurochemistry
Koppel I., Tuvikene J., Lekk I., Timmusk T. Efficient use of a translation start codon in BDNF exon I. J. Neurochem., 2015, 134,1015-1025.

https://onlinelibrary.wiley.com/doi/10.1111/jnc.13124

2014 Handbook of Experimental Pharmacology 
West A. E., Pruunsild P., Timmusk T. Neurotrophins: transcription and translation. Handb. Exp. Pharmacol., 2014, 220, 67-100.

https://link.springer.com/chapter/10.1007%2F978-3-642-45106-5_4

2014 Journal of Biological Chemistry 
Kannike K., Sepp M., Zuccato C., Cattaneo E., Timmusk T. Forkhead transcription factor FOXO3a levels are increased in Huntington disease because of overactivated positive autofeedback loop. J. Biol. Chem., 2014, 289, 32845-32857.

https://www.sciencedirect.com/science/article/pii/S0021925820474848?via%3Dihub

2013 Neuropharmacology
Koppel I., Timmusk T. Differential regulation of Bdnf expression in cortical neurons by class-selective histone deacetylase inhibitors. Neuropharmacology, 2013, 75, 106-115.

https://www.sciencedirect.com/science/article/pii/S0028390813003328?via%3Dihub

2012 Human Molecular Genetics
Sepp M., Pruunsild P., Timmusk T. Pitt-Hopkins Syndrome associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant negative effects. Hum. Mol. Genet., 2012, 21, 2873-2888.

https://academic.oup.com/hmg/article/21/13/2873/2900619

2011 PLoS ONE 
Sepp M., Kannike K., Eesmaa A., Urb M., Timmusk T. Functional diversity of human basic helix-loop-helix transcription factor TCF4 isoforms generated by alternative 5' exon usage and splicing. PLoS ONE, 2011, 6, e22138.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022138

2011 Journal of Neuroscience
Pruunsild P., Sepp M., Orav E., Koppel I., Timmusk T. Identification of cis-elements and transcription factors regulating neuronal activity-dependent transcription of human BDNF gene. J. Neurosci., 2011, 31, 3295-3308.

https://www.jneurosci.org/content/31/9/3295.long

Selection of earlier publications

2010 Journal of Neurochemistry
Luberg K., Wong J., Weickert C.S., Timmusk T. Human TrkB gene: novel alternative transcripts, protein isoforms and expression pattern in the prefrontal cerebral cortex during postnatal development. J. Neurochem., 2010, 113, 952-964.

2007 Genomics 
Pruunsild P, Kazantseva A, Aid T, Palm K, Timmusk T. Dissecting the human BDNF locus: bidirectional transcription, complex splicing and multiple promoters. Genomics, 2007, 90, 397-406.

2007 Journal of Neuroscience Research
Aid T., Kazantseva A., Piirsoo M., Palm K., Timmusk T. Mouse and rat BDNF gene structure and expression revisited. J Neurosci. Res, 2007, 85, 525-535.

2007 Nature
Lindholm P., Voutilainen M.H., Laurén J., Peränen J., Leppänen V.M., Andressoo J.O., Lindahl M., Janhunen S., Kalkkinen N., Timmusk T., Tuominen R.K., Saarma M. Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo. Nature, 2007, 448, 73- 77. 

2003 Nature Genetics 
Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., Conti, L., Cataudella, T., Leavitt, L., Hayden, M. R., Timmusk, T., Rigamonti D., Cattaneo, E. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nature Genetics, 2003, 35, 76-83.

2001 Science 
Zuccato, C., Ciammola, A., Rigamonti, D., Leavitt, B. R., Goffredo, D., Conti, L., MacDonald, M. E., Friedlander, R. M., Silani, V., Hayden, M. R., Timmusk, T., Sipione, S., Cattaneo, E. Loss of Huntingtin-Mediated BDNF gene transcription in Huntington's disease. Science, 2001, 293, 493-498.

1999 Journal of Biological Chemistry 
Timmusk T., Palm K., Lendahl U., Metsis M. Brain-derived neurotrophic factor expression in vivo is under the control of neuron-restrictive silencer element. J. Biol. Chem., 1999, 274, 1078-1084.

1998 Neuron 
Shieh P. B., Hu S.C., Bobb K., Timmusk T., Ghosh A. Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron, 1998, 20, 727-740.

1998 Journal of Neuroscience
Palm K., Belluardo N., Metsis M., Timmusk T. Neuronal expression of zinc finger transcription factor REST/NRSF/XBR gene. J. Neurosci., 1998, 18, 1280-1296.

1995 Journal of Cell Biology
Timmusk T., Lendahl U., Funakoshi H., Arenas E., Persson H., Metsis M. Identification of BDNF promoter regions mediating tissue-specific, axotomy- and neuronal activity-induced expression in transgenic mice. J. Cell Biol., 1995, 128, 185-199.

1993 European Journal of Neuroscience
Timmusk T., Belluardo N., Metsis M., Persson H. Widespread and developmentally regulated expression of neurotrophin-4 mRNA in rat brain and peripheral tissues. Eur. J. Neurosci., 1993, 5, 605-613.

1993 Neuron 
Timmusk T., Palm K., Metsis M., Reintam T., Paalme V., Saarma M., Persson H. Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron, 1993, 10, 475-489.

Astrocytes cells are one of the most abundant cell types in the central nervous system (CNS). They fulfil several important roles including ion homeostasis, neurotransmitter uptake and maintenance of the blood-brain barrier. It is known that neurons and astrocytes communicate with each other, using neurotransmitters (called gliotransmitters when coming from the astrocyte side) and other intercellular messengers.

In our group, we are interested in how selective activation of intracellular signaling pathways in either neurons or astrocytes will affect the physiology and gene expression in the other cell type.
To this end, we are using novel genetic tools for cell-specific pathway activation and transcriptome/proteome profiling.

Another topic we are interested in is the role of neurotrophins in non-neuronal cell types such as glial cells and cardiomyocytes.

Members of the group:

Dr. Indrek Koppel
Dr. Florencia Cabrera Cabrera

1: Doron-Mandel E, Koppel I, Abraham O, Rishal I, Smith TP, Buchanan CN, Sahoo
PK, Kadlec J, Oses-Prieto JA, Kawaguchi R, Alber S, Zahavi EE, Di Matteo P, Di
Pizio A, Song DA, Okladnikov N, Gordon D, Ben-Dor S, Haffner-Krausz R, Coppola
G, Burlingame AL, Jungwirth P, Twiss JL, Fainzilber M. The glycine arginine-rich
domain of the RNA-binding protein nucleolin regulates its subcellular
localization. EMBO J. 2021 Sep 13:e107158. doi: 10.15252/embj.2020107158. Epub
ahead of print. PMID: 34515347.

2: Mentrup T, Cabrera-Cabrera F, Schröder B. Proteolytic Regulation of the
Lectin-Like Oxidized Lipoprotein Receptor LOX-1. Front Cardiovasc Med. 2021 Jan
20;7:594441. doi: 10.3389/fcvm.2020.594441. PMID: 33553253; PMCID: PMC7856673.

3: Gradtke AC, Mentrup T, Lehmann CHK, Cabrera-Cabrera F, Desel C, Okakpu D,
Assmann M, Dalpke A, Schaible UE, Dudziak D, Schröder B. Deficiency of the
Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of
Dendritic Cells. J Immunol. 2021 Jan 1;206(1):164-180. doi:
10.4049/jimmunol.2000151. Epub 2020 Nov 25. PMID: 33239420.

4: Marvaldi L, Panayotis N, Alber S, Dagan SY, Okladnikov N, Koppel I, Di Pizio
A, Song DA, Tzur Y, Terenzio M, Rishal I, Gordon D, Rother F, Hartmann E, Bader
M, Fainzilber M. Importin α3 regulates chronic pain pathways in peripheral
sensory neurons. Science. 2020 Aug 14;369(6505):842-846. doi:
10.1126/science.aaz5875. PMID: 32792398.

5: Mentrup T, Cabrera-Cabrera F, Fluhrer R, Schröder B. Physiological functions
of SPP/SPPL intramembrane proteases. Cell Mol Life Sci. 2020
Aug;77(15):2959-2979. doi: 10.1007/s00018-020-03470-6. Epub 2020 Feb 12. PMID:
32052089; PMCID: PMC7366577.

6: Urb M, Anier K, Matsalu T, Aonurm-Helm A, Tasa G, Koppel I, Zharkovsky A,
Timmusk T, Kalda A. Glucocorticoid Receptor Stimulation Resulting from Early
Life Stress Affects Expression of DNA Methyltransferases in Rat Prefrontal
Cortex. J Mol Neurosci. 2019 May;68(1):99-110. doi: 10.1007/s12031-019-01286-z.
Epub 2019 Mar 9. PMID: 30852742.

7: Mentrup T, Theodorou K, Cabrera-Cabrera F, Helbig AO, Happ K, Gijbels M,
Gradtke AC, Rabe B, Fukumori A, Steiner H, Tholey A, Fluhrer R, Donners M,
Schröder B. Atherogenic LOX-1 signaling is controlled by SPPL2-mediated
intramembrane proteolysis. J Exp Med. 2019 Apr 1;216(4):807-830. doi:
10.1084/jem.20171438. Epub 2019 Feb 28. PMID: 30819724; PMCID: PMC6446863.

8: Koppel I, Fainzilber M. Omics approaches for subcellular translation studies.
Mol Omics. 2018 Dec 3;14(6):380-388. doi: 10.1039/c8mo00172c. PMID: 30338329.

9: Rozenbaum M, Rajman M, Rishal I, Koppel I, Koley S, Medzihradszky KF, Oses-
Prieto JA, Kawaguchi R, Amieux PS, Burlingame AL, Coppola G, Fainzilber M.
Translatome Regulation in Neuronal Injury and Axon Regrowth. eNeuro. 2018 May
10;5(2):ENEURO.0276-17.2018. doi: 10.1523/ENEURO.0276-17.2018. PMID: 29756027;
PMCID: PMC5944006.

10: Terenzio M, Koley S, Samra N, Rishal I, Zhao Q, Sahoo PK, Urisman A, Marvaldi
L, Oses-Prieto JA, Forester C, Gomes C, Kalinski AL, Di Pizio A, Doron-Mandel E,
Perry RB, Koppel I, Twiss JL, Burlingame AL, Fainzilber M. Locally translated
mTOR controls axonal local translation in nerve injury. Science. 2018 Mar
23;359(6382):1416-1421. doi: 10.1126/science.aan1053. PMID: 29567716; PMCID:
PMC6501578.

11: Koppel I, Jaanson K, Klasche A, Tuvikene J, Tiirik T, Pärn A, Timmusk T.
Dopamine cross-reacts with adrenoreceptors in cortical astrocytes to induce BDNF
expression, CREB signaling and morphological transformation. Glia. 2018
Jan;66(1):206-216. doi: 10.1002/glia.23238. Epub 2017 Oct 6. PMID: 28983964.

12: Jaagura M, Taal K, Koppel I, Tuvikene J, Timmusk T, Tamme R. Rat NEURL1 3'UTR
is alternatively spliced and targets mRNA to dendrites. Neurosci Lett. 2016 Dec
2;635:71-76. doi: 10.1016/j.neulet.2016.10.041. Epub 2016 Oct 22. PMID:
27780737.

13: Tucci P, Estevez V, Becco L, Cabrera-Cabrera F, Grotiuz G, Reolon E, Marín M.
Identification of Leukotoxin and other vaccine candidate proteins in a
<i>Mannheimia haemolytica</i> commercial antigen. Heliyon. 2016 Sep
19;2(9):e00158. doi: 10.1016/j.heliyon.2016.e00158. PMID: 27699279; PMCID:
PMC5035357.

14: Fernández-Calero T, Cabrera-Cabrera F, Ehrlich R, Marín M. Silent
Polymorphisms: Can the tRNA Population Explain Changes in Protein Properties?
Life (Basel). 2016 Feb 17;6(1):9. doi: 10.3390/life6010009. PMID: 26901226;
PMCID: PMC4810240.

15: Koppel I, Tuvikene J, Lekk I, Timmusk T. Efficient use of a translation start
codon in BDNF exon I. J Neurochem. 2015 Sep;134(6):1015-25. doi:
10.1111/jnc.13124. Epub 2015 Apr 27. PMID: 25868795.

16: Garcia-Silva MR, Sanguinetti J, Cabrera-Cabrera F, Franzén O, Cayota A. A
particular set of small non-coding RNAs is bound to the distinctive Argonaute
protein of Trypanosoma cruzi: insights from RNA-interference deficient
organisms. Gene. 2014 Apr 1;538(2):379-84. doi: 10.1016/j.gene.2014.01.023. Epub
2014 Jan 23. PMID: 24463018.

17: Garcia-Silva MR, Cabrera-Cabrera F, das Neves RF, Souto-Padrón T, de Souza
W, Cayota A. Gene expression changes induced by Trypanosoma cruzi shed
microvesicles in mammalian host cells: relevance of tRNA-derived halves. Biomed
Res Int. 2014;2014:305239. doi: 10.1155/2014/305239. Epub 2014 Apr 9. PMID:
24812611; PMCID: PMC4000953.

18: Koppel I, Timmusk T. Differential regulation of Bdnf expression in cortical
neurons by class-selective histone deacetylase inhibitors. Neuropharmacology.
2013 Dec;75:106-15. doi: 10.1016/j.neuropharm.2013.07.015. Epub 2013 Aug 2.
PMID: 23916482.

19: Garcia-Silva MR, das Neves RF, Cabrera-Cabrera F, Sanguinetti J, Medeiros LC,
Robello C, Naya H, Fernandez-Calero T, Souto-Padron T, de Souza W, Cayota A.
Extracellular vesicles shed by Trypanosoma cruzi are linked to small RNA
pathways, life cycle regulation, and susceptibility to infection of mammalian
cells. Parasitol Res. 2014 Jan;113(1):285-304. doi: 10.1007/s00436-013-3655-1.
Epub 2013 Nov 17. PMID: 24241124.

20: Garcia-Silva MR, Cabrera-Cabrera F, Güida MC, Cayota A. Hints of tRNA-Derived
Small RNAs Role in RNA Silencing Mechanisms. Genes (Basel). 2012 Oct
10;3(4):603-14. doi: 10.3390/genes3040603. PMID: 24705078; PMCID: PMC3899978.

21: Pruunsild P, Sepp M, Orav E, Koppel I, Timmusk T. Identification of cis-
elements and transcription factors regulating neuronal activity-dependent
transcription of human BDNF gene. J Neurosci. 2011 Mar 2;31(9):3295-308. doi:
10.1523/JNEUROSCI.4540-10.2011. PMID: 21368041; PMCID: PMC6623925.

22: Koppel I, Aid-Pavlidis T, Jaanson K, Sepp M, Palm K, Timmusk T. BAC
transgenic mice reveal distal cis-regulatory elements governing BDNF gene
expression. Genesis. 2010 Apr;48(4):214-9. doi: 10.1002/dvg.20606. PMID:
20186743; PMCID: PMC2978326.

23: Koppel I, Aid-Pavlidis T, Jaanson K, Sepp M, Pruunsild P, Palm K, Timmusk T.
Tissue-specific and neural activity-regulated expression of human BDNF gene in
BAC transgenic mice. BMC Neurosci. 2009 Jun 25;10:68. doi:
10.1186/1471-2202-10-68. PMID: 19555478; PMCID: PMC2708170.

24: Mällo T, Kõiv K, Koppel I, Raudkivi K, Uustare A, Rinken A, Timmusk T, Harro
J. Regulation of extracellular serotonin levels and brain-derived neurotrophic
factor in rats with high and low exploratory activity. Brain Res. 2008 Feb
15;1194(5):110-7. doi: 10.1016/j.brainres.2007.11.041. Epub 2007 Dec 4. PMID:
18177844; PMCID: PMC2568862.

25: Francks C, Maegawa S, Laurén J, Abrahams BS, Velayos-Baeza A, Medland SE,
Colella S, Groszer M, McAuley EZ, Caffrey TM, Timmusk T, Pruunsild P, Koppel I,
Lind PA, Matsumoto-Itaba N, Nicod J, Xiong L, Joober R, Enard W, Krinsky B,
Nanba E, Richardson AJ, Riley BP, Martin NG, Strittmatter SM, Möller HJ, Rujescu
D, St Clair D, Muglia P, Roos JL, Fisher SE, Wade-Martins R, Rouleau GA, Stein
JF, Karayiorgou M, Geschwind DH, Ragoussis J, Kendler KS, Airaksinen MS,
Oshimura M, DeLisi LE, Monaco AP. LRRTM1 on chromosome 2p12 is a maternally
suppressed gene that is associated paternally with handedness and schizophrenia.
Mol Psychiatry. 2007 Dec;12(12):1129-39, 1057. doi: 10.1038/sj.mp.4002053. Epub
2007 Jul 31. PMID: 17667961; PMCID: PMC2990633.

Infertility is a global problem affecting approximately 15% of all couples in a fertile age. While there are many causes for both male and female infertility, possible treatments are fortunately similarly numerous. One common method enabling otherwise infertile couples to receive genetically their own offspring is in vitro fertilization (IVF). Sadly, the efficiency of IVF is low – on average only one in three procedures culminates in the birth of a child.

The Research Group for Reproductive Biology studies the molecular mechanisms behind fertility and infertility. We are focused foremost on female infertility and on such ovarian processes which assure the maturation of a healthy egg cell. This maturation is affected by hormones from the pituitary gland, steroid hormones produced by the ovaries and several different signaling molecules that move between the egg cell and the granulosa cells surrounding it. By identifying key signaling pathways for egg cell maturation in granulosa cells we can use these cells for diagnostics and thus greatly improve the effectiveness of the IVF procedure.

The ovarian follicle is the main research object in our group. As the oocyte is used for fertilization and embryo development during IVF procedures, invasive methods to study its ingredients are not preferable. However, the environment of oocyte maturation can be evaluated by investigating its surrounding granulosa cells and the follicular fluid that contain a lot of genetic and biochemical information.
   
In our work we use both classical laboratory methods as well as methods for high throughput analysis (such as analyzing gene expression by deep sequencing, microchip or mass spectrometry methods). In addition, we perform bioinformatical data analysis, biostatistics and modelling signaling pathways.

We are in close cooperation with the Competence Centre on Health Technologies (Tervisetehnoloogia Arenduskeskus AS) and with all fertility clinics in Estonia.

Group members:
Agne Velthut-Meikas, PhD, Associate professor, principal investigator
Kristine Roos, MSc, PhD student
Inge Varik, MSc, PhD student
Mai-Ly Kristal, BSc, MSc student
Margit Paukson, BSc, MSc student
Katariina Johanna Saretok, BSc student

GROUP WEBSITE

Link to publications

We join the specialists from various departments, universities, and private sector, aiming to ensure groundbreaking research can be turned into successful business opportunities. Over the last 15 years we have successfully developed various analyzers (TRL6-7) for different partners (e.g. Estonian Police and Border Guard). Our core technologies are Capillary Electrophoresis, Fluorescence, Conductivity, Gas Chromatography, Microfluidics, and other instrumental and analytical techniques. We collaborate with various research groups worldwide, providing our competence for successful participation in Horizon Europe and other various open calls.

Visit Drug Hunter Analyzer’ website for more information about drug analysis in oral fluid www.drughunter.eu

People

Group leader - Dr. Jekaterina Mazina-Šinkar (jekaterina.mazina@taltech.ee),
Dr. Jelena Gorbatšova,
Dr. Evelin Halling,
Professor emeritus Mihkel Kaljurand,
Dr. Merike Vaher,
Dr. Martin Ruzicka,
Vyacheslav Bolkvadze,
Jana Budkovskaja

https://orcid.org/0000-0002-2430-0097, 

https://orcid.org/0000-0002-5903-6337, 

https://orcid.org/0000-0003-2289-188X