Research of the Institute of Biomedicine and Translational Medicine

The Institute of Biomedicine and Translational Medicine at the University of Tartu is a research and education institute in biomedical sciences. The research areas include basic and translational medicine.The mission is to create an internationally high standard research and education institute operating in the field of biomedicine.

The specific research projects are given at homepages of each work group:

 

Read more about the research of the Department of Biochemistry.

 

Project: Center of Excellence for Genomics and Translational Medicine (Archimedes Foundation, SMVBS16142T)
Period: 01.01.2016−01.03.2023
Contact: Professor Mihkel Zilmer
E-mail: mihkel.zilmer@ut.ee

The CoE for Genomics and Translational Medicine aims to translate discoveries in the field of genomics into improved understanding of molecular mechanisms of disease. The new interdisciplinary environment of the CoE makes it possible to interpret and rapidly utilize data produced by cutting edge omics technologies. The Centre will explore genetic and biolological mechanisms of disease by 1) investigating DNA sequence variants that contribute to disease through large scale genomic screens, and 2) using molecular and cellular bology techniques complemented by the use of animal models to study their role in disease. This offers an exciting platform for discovering important biological mechanisms that contribute to disease. The outputs of the project are anticipated to unravel processes underlying complex disease, identify new therapeutic targets and enable development of new approaches for disease prevention and precision medicine that will have a major impact in Europe and globally.

 

Read more about of the Department of Pharmacology.

 

Project: Center of Excellence for Genomics and Translational Medicine (Archimedes Foundation, SMVBS16142T)
Period: 01.01.2016−01.03.2023
Contact: Professor Allen Kaasik
E-mail: allen.kaasik@ut.ee

The CoE for Genomics and Translational Medicine aims to translate discoveries in the field of genomics into improved understanding of molecular mechanisms of disease. The new interdisciplinary environment of the CoE makes it possible to interpret and rapidly utilize data produced by cutting edge omics technologies. The Centre will explore genetic and biolological mechanisms of disease by 1) investigating DNA sequence variants that contribute to disease through large scale genomic screens, and 2) using molecular and cellular bology techniques complemented by the use of animal models to study their role in disease. This offers an exciting platform for discovering important biological mechanisms that contribute to disease. The outputs of the project are anticipated to unravel processes underlying complex disease, identify new therapeutic targets and enable development of new approaches for disease prevention and precision medicine that will have a major impact in Europe and globally.

 

Project: Mitochondrial dysfunction in axonal damage (Estonian Research Council, GMVBS0400PR)
Period: 01.01.2019−31.12.2023
Contact: Professor Allen Kaasik
E-mail: allen.kaasik@ut.ee

Axonal regeneration in the adult central nervous system is extremely limited after injury. As a consequence, there is typically little functional recovery after spinal cord injury, traumatic brain injury, or stroke and related conditions that involve axonal damage and disconnection. Recent discoveries suggest that local ATP supply is critical for axon regeneration. In order to recover, the neuron must summon enough healthy mitochondria with high membrane potential to the site of the injury. The main aim is to elucidate the role of mitochondria in axonal injury and to find a way to promote neuronal recovery. We will build a magneto-microfluidic system for modelling and investigating the axonal injury in neuronal cultures and study what exactly happens with mitochondria during and after the axonal injury. Our aim will be to identify small molecule compounds to increase mitochondrial density in the sire of injury and limit axonal damage or/and improve the recovery.

 

Project: Unraveling the molecular mechanisms underlying Ca2+-signaling modulation by CISD2, a wolfram syndrome-associated gene, and its interplay with Bcl-2 (Flemish Research Council, MMVBS21348)
Period: 01.01.2021−31.12.2024
Contact: Professor Allen Kaasik
E-mail: allen.kaasik@ut.ee

The endoplasmic reticulum (ER) plays a key role in intracellular Ca2+ signaling. Dysregulation of these signals underly several diseases, including Wolfram syndrome, a condition associated with mutations in WFS1 en CISD2, resulting in neuronal defects and juvenile diabetes. Until now, no cure for Wolfram syndrome is available. Moreover, CISD2 has been identified as a longevity-associated gene.
Previous studies by others have linked CISD2 deficiency to deranged Ca2+ signalling, though the molecular basis remains unclear. Also, CISD2 can target the anti-apoptotic/anti-autophagic protein Bcl-2, promoting its cellular function. The Bcl-2 domain targeted by CISD2 is the BH4 domain. Fascinatingly, we previously showed Bcl-2’s BH4 domain binds to and inhibits IP3 and ryanodine receptors (IP3Rs and RyRs), intracellular Ca2+-release channels whose function is disturbed in Wolfram syndrome.
Here, we aim to investigate the mechanisms by which CISD2 modulates intracellular Ca2+ dynamics by controlling the Ca2+-flux properties of IP3Rs and RyRs and this property is affected by disease-linked mutations in CISD2. We will consider both direct modulation of these channels by CISD2 as well as indirect modulation through Bcl-2’s BH4 domain. These studies will be expanded towards cell models relevant for Wolfram syndrome. We envision that this work can contribute to a better understanding of the etiology of CISD2-linked Wolfram syndrome and may provide novel therapeutic strategies to tackle this disease.

 

Project: Exploration of the therapeutic potential of the active vitamin D analogues: focus on the mood disorders and obesity (Estonian Research Council, GMVBS20080PR)
Period: 01.01.2010−31.12.2024
Contact: Professor Aleksandr Žarkovski
E-mail: aleksandr.zarkovski@ut.ee

The active vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), plays an important role in calcium homeostasis, cell differentiation, immunity, neurodegenerative diseases, depression and obesity. The calcemic effect of 1,25(OH)2D3 and its derivatives has limited their clinical application. The main goal of this project is to explore the therapeutic potential of the synthetic analogue of vitamin D, elocalcitol in the models of (1) depression and (2) obesity. The results of this project will provide new knowledge on the therapeutic potential of elocalcitol in obesity and depression. New knowledge on the safety and molecular mechanisms of the action elocalcitol will be generated. The data may lead to the development of novel intervention strategies in patients with depression or obesity. Demonstration of the antidepressant- and/or anti-obese efficacy will form the basis for the further clinical studies to evaluate the effects of active vitamin D analogues in patients.

 

Project: Development of curricula via international collaboration (Educational and Youth Board, DMVBS19558)
Period: 15.10.2019−14.10.2023
Contact: Associate Professor Miriam Ann Hickey
E-mail: miriam.ann.hickey@ut.ee

Medical governing bodies require that modern medical graduates show many transferable skills; indeed, the Estonian Ministry of Education recently introduced a framework “approach to learning” to guide practitioners in the qualities that modern students must develop through their education. Within this cooperation program, the University of Tartu and University of Iceland will collaborate to provide unique opportunities to our medical undergraduates to travel to a foreign country and complete short research projects in basic science for curriculum credits. In completing this project, our students will learn valuable skills, including communication, leadership, team work and critically, the importance of basic science to medicine. We firmly believe that this cooperation program will provide exceptional opportunities to our undergraduates to enhance their knowledge of the scientific process, which is unfortunately poor and even lacking in our current curriculum.

 

Project: The effect of DNA methyltransferase-inhibitor treatment on aberrant DNA methylation in human leukocytes: A novel pharmacological strategy for treatment of psychostimulant-induced drug addiction (Estonian Research Council, GMVBS22063PR)
Period: 01.01.2022−31.12.2026
Contact: Professor Anti Kalda
E-mail: anti.kalda@ut.ee

Currently, there is no cure for psychostimulant-induced drug addiction. Several studies have evaluated the reversal of psychostimulant addiction using dopaminergic, serotoninergic, glutamatergic, and GABAergic strategies. Unfortunately, clinical data remain disappointing, and novel pharmacological strategies are needed. Therefore, the main goal of this project is to investigate a new drug candidate - DNA methyltransferase (DNMT) inhibitor effects on psychostimulant-induced addiction. We will study: 1) aberrant DNA methylation and long-term epigenetic-mediated gene expression changes in human leukocytes following repeated exposure to psychostimulants; 2) how psychostimulant-treated leukocytes alter neuroplasticity of an addicted brain; 3) whether DNMT-inhibitor treatment inhibits psychostimulant-induced changes in leukocytes and how these changes affect brain neuroplasticity. The results of this project may help to find new biomarkers and to develop novel treatments for drug addiction.

 

Read more about of the Department of Physiology.

 

Project: Center of Excellence for Genomics and Translational Medicine (Archimedes Foundation, SMVBS16142T)
Period: 01.01.2016−01.03.2023
Contact: Professor Eero Vasar
E-mail: eero.vasar@ut.ee

The CoE for Genomics and Translational Medicine aims to translate discoveries in the field of genomics into improved understanding of molecular mechanisms of disease. The new interdisciplinary environment of the CoE makes it possible to interpret and rapidly utilize data produced by cutting edge omics technologies. The Centre will explore genetic and biolological mechanisms of disease by 1) investigating DNA sequence variants that contribute to disease through large scale genomic screens, and 2) using molecular and cellular bology techniques complemented by the use of animal models to study their role in disease. This offers an exciting platform for discovering important biological mechanisms that contribute to disease. The outputs of the project are anticipated to unravel processes underlying complex disease, identify new therapeutic targets and enable development of new approaches for disease prevention and precision medicine that will have a major impact in Europe and globally.

Project: Potential biomarkers for the diagnosis, prognosis, and evaluation of treatment impact for first episode psychosis and schizophrenia spectrum disorders: translational approach (Estonian Research Council, GMVBS20067PR)
Period: 01.01.2020−31.12.2024
Contact: Professor Eero Vasar
E-mail: eero.vasar @ut.ee

The main goal is to explain the peculiarities of first episode psychosis (FEP) and possibilities for personal treatment. First, metabolomic, oxidative stress and inflammation markers in subjects with 5-year illness will be compared with respective parameters at disease onset and after 6-7-month antipsychotic treatment (APT). This approach is necessary to determine why many patients develop metabolic syndrome (MetS): overweight, shift in insulin sensitivity, and elevated inflammation and oxidative stress. In the second part, the effect of adjuvant treatment with GLP-1 agonist liraglutide on the development of MetS is studied in FEP patients. We assume that it helps to delay/prevent APT-induced MetS. In parallel, we study the possible involvement of Negr1, a psychiatric risk gene, in the development of APT-caused metabolic shifts, using mice lacking Negr1 gene to highlight new genetic and metabolic links between psychiatric disorders and the development of MetS.

The research projects of the Department of Biomedicine 

 

Read more about the research of the Molecular Pathology Research Group.

 

Project: Central immune tolerance (Estonian Research Council, GMVBS0377PR)
Period: 01.01.2019−31.12.2023
Contact: Professor Pärt Peterson  
E-mail: part.peterson@ut.ee

Central immune tolerance of T cells is established in the thymus. An important factor in the thymic immune tolerance is autoimmune regulator (AIRE) that in thymic medullary epithelium promotes the selection of developing T cells. During recent years, many key findings have advanced our understanding how the immune tolerance to self-antigens is achieved. Nevertheless, several mechanistic aspects of the central tolerance have remained enigmatic. In this proposal, we will study the role of Aire and thymic medullary epithelium in promiscuous self-antigen expression; the homeostatic regulators in the thymus function and the anti-cytokine autoantibodies developed by human patients with AIRE mutations. Our research will provide new insights into the tolerance mechanisms, with a particular relevance to the understanding how autoimmune attack to body tissues is avoided, but also has a potential in development of therapeutic monoclonal antibodies.

 

Project: Center of Excellence for Genomics and Translational Medicine (Archimedes Foundation, SMVBS16142T)
Period: 01.01.2016−01.03.2023
Contact: Professor Pärt Peterson
E-mail: part.peterson@ut.ee

The CoE for Genomics and Translational Medicine aims to translate discoveries in the field of genomics into improved understanding of molecular mechanisms of disease. The new interdisciplinary environment of the CoE makes it possible to interpret and rapidly utilize data produced by cutting edge omics technologies. The Centre will explore genetic and biolological mechanisms of disease by 1) investigating DNA sequence variants that contribute to disease through large scale genomic screens, and 2) using molecular and cellular bology techniques complemented by the use of animal models to study their role in disease. This offers an exciting platform for discovering important biological mechanisms that contribute to disease. The outputs of the project are anticipated to unravel processes underlying complex disease, identify new therapeutic targets and enable development of new approaches for disease prevention and precision medicine that will have a major impact in Europe and globally.

 

Project: Type I interferons and their autoantibodies in autoimmunity and COVID-19 (Estonian Research Council, GMVBS21081PR) 
Period: 01.01.2021−31.12.2025
Contact: Professor Kai Kisand
E-mail: kai.kisand@ut.ee

Type I IFNs are immune mediators that are known for their anti-viral properties. At the same time, their dysregulated production is associated with pathology. Type I IFNs are implicated in the development of disorders of major disease burden, many of which are currently lacking cure - systemic lupus erythematosus, type I diabetes, Alzheimer's disease to name only a few. The role of type I IFNs in COVID-19 is also not known. While type I IFNs can be protective in the initial phases of the disease they may amplify the cytokine storm in the severely ill patients. The current project expects to gain detailed knowledege about the effect of type I IFNs to various immune cells and find the ways to mitigate their potential to amplify autoimmunity and exuberant inflammation.

 

Project: Impaired thymic negative selection as a source of melanoma-reactive TCR specificities (LEO Foundation, MMVBS18294)
Period: 01.08.2018−30.04.2023
Contact: Professor Kai Kisand
E-mail: kai.kisand@ut.ee

Melanoma is a very aggressive type of cancer that affects people at their most productive period of the life. As most of the diagnosed patients should have a long life still ahead a cure of the disease is highly desired. Cancer immunotherapy with checkpoint inhibitors and T cell adoptive therapy have established the crucial role of T cell responses in melanoma as well as in many other cancers. Successful immunotherapy of melanoma is often associated with vitiligo as a side effect indicating the importance of targeting the antigenic epitopes that are shared between melanocytes and melanoma cells. However, melanocyte antigens are “self” and T cell receptor (TCR) specificities that recognise such epitopes with high affinity are deleted during their maturation in the thymus. To find high-affinity TCRs specific for melanocyte/melanoma antigens we will interrogate the TCR repertoire of a patient population that is defective in their central (thymic) tolerance induction mechanisms due to mutations in autoimmune regulator gene, and who develop vitiligo as one of their disease manifestations. We expect to identify several TCR specificities that recognise melanocyte/melanoma antigenic epitopes. This information can be used for designing genetically modified T cells for adoptive treatment of melanoma patients, and to advance the knowledge about vitiligo pathogenesis and mechanisms of central tolerance induction.

 

Project: Thymic Abnormalities in Rare Immunological Diseases (Ministry of Social Affairs, SMVBS20416) 
Period: 01.09.2020−31.08.2023
Contact: Professor Pärt Peterson
E-mail: part.peterson@ut.ee

Many rare diseases are caused by a malfunctioning immune system attacking the patient's own tissues, but treatment options are limited by the fact that the origin of such malfunctioning is poorly understood. In the TARID project we study some of these immunological diseases, united by similar pathogenetic events and pathological findings. Our ultimate goal is to provide information facilitating the development and use of new modes of treatment in rare immunological diseases.

 

Project: European Network Linking Informatics and Genomics of Helper T cells in Tissues (European Commission Horizon2020, MSCA Enlighten+, MMVBS21006R)
Period: 01.03.2021−28.02.2025
Contact: Professor Pärt Peterson 
E-mail: part.peterson@ut.ee

ENLIGHT-TEN+ is a European Network Linking Informatics and Genomics of Helper T cells in Tissues: A crucial missing link in our current research environment is the lack of qualified individuals who possess the immunology skills to recognise and
define important scientific questions amenable to -omics approaches, and also the bioinformatic expertise to interrogate and interpret the resulting Big Data appropriately. Thus, our mission is to provide cross-disciplinary training for a new generation
of enthusiastic researchers who have in-depth understanding of T cell immunology and are also capable to handle large datasets. Our network of 15 beneficiaries from 10 European countries combines expertise on T cell biology with state-of-theart technologies generating Big Data, cutting-edge bioinformatic tools including artificial intelligence, preclinical models and samples from patient cohorts. ENLIGHT-TEN+ will identify microenvironmental factors shaping the functional properties of
tissue-resident T cells, which offer important therapeutic potential in various human autoimmune diseases, making them a key target for pharmaceutical companies. 15 early-stage researchers (ESRs) will be empowered to push our knowledge of
tissue-resident T cells beyond the state-of-the-art which will enable the identification of novel biomarkers and support the development of advanced therapeutic concepts. The generation of Big Data is an emerging and challenging field, and there is high demand in both the academic and industrial sector for researchers to be able to analyse, integrate and exploit this rich source of information. ENLIGHT-TEN+ will combine individual strengths of innovative laboratories and enterprises from complementary disciplines to provide unique interdisciplinary training as an ideal stepping-stone for the ESRs to enter and
strengthen Europe’s academia as well as pharmaceutical and bioinformatics companies, thereby placing them at the forefront of this emerging field.

 

Project: Molecular mechanisms underlying impaired antiviral cytotoxic T cell responses in old age (Estonian Research Council, SMVBS21533)
Period: 01.12.2021−30.11.2023
Contact: Research Fellow Maarja Laos 
E-mail: maarja.laos@ut.ee

The world´s population, including Estonia, is aging, which can create specific challenges and burdens on the healthcare system. Age-related impairment of immune responses leads to increased susceptibility to infections in older people, especially to new and emerging pathogens such as the current COVID-19 causing SARS-CoV-2 virus. In this project I will study in-depth the intrinsic properties of CD8+ cytotoxic T cells from older individuals and assess why their activation capacity to different viruses (influenza, SARS-CoV-2) declines. The results from this project will allow us to better predict to what degree vaccination can offer protection to older individuals, which is particularly relevant in the current SARS-CoV-2 pandemic. Furthermore, the obtained data will be used to develop new strategies to boost vaccine efficacy and the aging immune system, and has the potential to influence public policy and healthcare priorities that can directly impact Estonia`s aging society.

 

Project: Longitudinal study: immune responses following COVID-19 immunization and SARS-CoV-2 infection (Republic of Estonia Ministry of Education and Research, SMVPT21607T) 
Period: 01.10.2021−30.06.2023
Contact: professor Pärt Peterson 
E-mail: part.peterson@ut.ee

The objective of the study is to assess the need for booster doses of COVID-19 vaccines.
The specific aims are: to assess the persistence of immunity after COVID-19 vaccination and the factors influencing it among the adult population in Estonia, and to assess the persistence of immunity after SARS-CoV-2 infection and the factors influencing it in the Estonian adult population.

 

Read more about the research of the Laboratory of Precision and Nanomedicine.

 

Project: LDL-like nanoparticles for CAR-T-based glioblastoma immunotherapy (Estonian Research Council, SMVBS21620)
Period: 13.12.2021−12.12.2024
Contact: Professor Tambet Teesalu
E-mail: tambet.teesalu@ut.ee

This project aims to demonstrate that the targeted delivery of exogenous antigens to the extracellular matrix (ECM) of brain tumors provides a safe and specific target for chimeric antigen receptor T-cell (CART) for the treatment of glioblastoma (GBM). GBM is the most common brain tumor in adults and despite all the advances combining surgery, chemotherapy and radiotherapy, it is still a disease with no cure. CART therapy is one of the most promising approaches in the treatment of GBM. The main obstacle limiting CART efficacy is the scarcity of highly expressed tumor antigens in GBM. In this regard, the ECM could provide a niche for abundant antigens suitable for activating CART; nonetheless, as these antigens are also present in healthy tissues, including the brain, a direct target by CART would lead to severe side effects.
In this project, we hypothesize that the components of the ECM could become ideal targets for CART therapy if labelled with FITC-peptides, enabling a tumor treatment using CART directed to FITC (FITC-CART). Therefore, we propose to deliver FITC-peptides to the ECM by incorporating these conjugates in small nanoparticles that mimic low-density lipoproteins (LDLNP), taking advantage of the known capacity of LDL to accumulate into brain tumors. The nanoparticle-based delivery of exogenous antigens will promote local accumulation of antigens in the tumor avoiding unspecific antigen build-up in healthy organs, which will result in the activation of CART only at the ECM of brain tumors.
This project describes an original approach for the treatment of GBM using CART therapy. Building upon the collective expertise of the consortium, this project will 1) Identify new peptides with selective affinity for the ECM of brain tumors; 2) synthesize FITC-peptide loaded LDLNP 3) deliver and release the FITC-peptides at the tumor ECM 4) produce and deliver FITC-CART to ECM 5) study the therapeutic efficacy of the CART activated by FITC-peptides in GBM animal models.

 

Project: Reactivation of antitumor immune responses in gliomas using nanotechnology based targeted delivery (Estonian Research Council, SMVBS20627)
Period: 21.12.2020−31.12.2023
Contact: Professor Tambet Teesalu
E-mail: tambet.teesalu@ut.ee

Glioblastoma (GBM) is the most common and aggressive brain cancer, for which the current standard of care is poorly efficacious. Immunotherapy using immune checkpoint inhibitors is emerging as a revolutionary approach to completely eradicate cancer. However, GBM patients respond poorly to immunotherapies as GBM is immunologically a “cold” tumor with low infiltration of functional T and NK cells. The immunosuppressive microenvironment in the GBM is created by the malignant cells and tumor-associated myeloid cells, such as resident brain macrophages and recruited monocytic cells. We propose to develop smart nanocarrier systems to deliver immunomodulatory agents to reactivate immune responses in GBM in order to sensitize GBM to immunotherapies. Specifically, in this project, we will develop nanovectors to deliver small interfering RNA (siRNA) 1) to revive cytolytic activities of NK cells, and 2) to modify tumorassociated myeloid cells to block their pro-tumoral differentiation and immunosuppressive functions. As the nanocarriers, the consortium will develop liposome, polymersome and dendrimer nanofomulations functionalized with homing peptides for effective crossing of the BBB and for specific targeting of immune cells in tumor microenvironment. These nanosystems will be evaluated for their ability to deliver siRNA, toxicity, and immunomodulatory activity both in vitro and in vivo. The most promising candidate nanocarriers will be tested for anti-GBM activity in clinically relevant models in mice. The success of this project will validate the proof-of-concept of therapeutic awakening of the GBM microenvironment using therapeutic siRNAs and provide a smart immunomodulatory nanosystem for downstream Investigational New Drug-enabling preclinical, scale-up, and regulatory studies. The project is highly likely to result in generation of clinically relevant Intellectual Property, as well as data of general interest for the cancer research community

 

Project: Peptide-targeted nanoparticles for delivery of therapeutics to tuberculosis (Bill and Melinda Gates Foundation, MMVBS21410)
Period: 07.04.2021−30.04.2023
Contact: Professor Tambet Teesalu
E-mail: tambet.teesalu@ut.ee

One of the main obstacles in treatment of tuberculosis is poor penetration of drugs to the lesions harboring the bacteria. We propose to overcome this problem by developing new technology based on peptides that specifically recognize and home to TB- infected tissue and/or the TB bacilli, penetrate the tissue barriers protecting the bacilli, and are capable of carrying therapeutic nanoparticles to the infected tissue.

 

Project: Hemoglobin based Protein Nanocarriers for Tumour Oxygenation and a more effective Photodynamic Therapy (European Commission, MMVBS18435R)
Period: 01.03.2019−28.02.2023 
Contact: Professor Tambet Teesalu
E-mail: tambet.teesalu@ut.ee

A major drawback of Photodynamic Therapy (PDT) and other therapies for cancer treatment is the limited oxygen content,hypoxia, in tumour tissue. In PDT a photosensitizing molecule is delivered to malignant tissue to generate radical oxygen species (ROS). The presence of oxygen is fundamental for ROS generation, ultimately causing the death of tumour cells. This project aims to develop hemoglobin drug delivery nanocarriers in the nano and submicron range for simultaneous oxygen and photosensitizer delivery to tumour tissue for a more efficient Photodynamic Therapy.
Hemoglobin-based nanocarriers (HOBCs) will be prepared by co-precipitation of hemoglobin with carbonates and surface coating with bovine serum albumin. The carriers will transport oxygen complexed to hemoglobin while photosensitizer molecules will be entrapped in the core. Carriers will be modified with homing peptides to target them to cancer cells. In vitro studies will be conducted to study the uptake of HOBCs by cells, their intracellular fate, toxicity, and oxygen and photosensitizer delivery. In vivo fate of carriers will be studied in mice with radiolabeled carriers by Positron Emission Tomography and Single Emission Computer Tomography. The efficiency of the HOBCs for oxygen delivery and for PDT will be tested in vitro and in vivo in breast and skin cancer models.
A multidisciplinary team has been gathered with scientists at the forefront of Material Science, Self assembly, Physics, Chemistry, Imaging, Molecular Biology and Cancer Therapy from Germany, Estonia, Spain, Brazil, Argentina and Thailand.
The participation of a SME will be fundamental for the future commercialization of project developments. OXIGENATED will actively work towards exchanging skills and knowledge through secondments of Early Stage and Experienced Researchers, and through networking and training activities. Seconded researchers will develop new scientific and complementary skills while exposed to new research environments.

 

Project: Center of Excellence for Genomics and Translational Medicine (Archimedes Foundation, SMVBS16142T)
Period: 01.01.2016−01.03.2023
Contact: Professor Tambet Teesalu
E-mail: tambet.teesalu@ut.ee

The CoE for Genomics and Translational Medicine aims to translate discoveries in the field of genomics into improved understanding of molecular mechanisms of disease. The new interdisciplinary environment of the CoE makes it possible to interpret and rapidly utilize data produced by cutting edge omics technologies. The Centre will explore genetic and biolological mechanisms of disease by 1) investigating DNA sequence variants that contribute to disease through large scale genomic screens, and 2) using molecular and cellular bology techniques complemented by the use of animal models to study their role in disease. This offers an exciting platform for discovering important biological mechanisms that contribute to disease. The outputs of the project are anticipated to unravel processes underlying complex disease, identify new therapeutic targets and enable development of new approaches for disease prevention and precision medicine that will have a major impact in Europe and globally.

 

Read more about the research of the RNA Biology Research Group.

 

Project: Adjustment of tissue-specific immune responses in chronic inflammatory diseases by miRNAs (Estonian Research Council, GMVBS21063PR)
Period: 01.01.2021−31.12.2025
Contact: Professor Ana Rebane  
E-mail: ana.rebane@ut.ee

Chronic inflammatory diseases, including atopic dermatitis (AD), psoriasis (Ps) and asthma constitute a substantial proportion of diagnoses in all health care levels, but current treatments for these diseases are not always effective. MicroRNAs (miRNAs) are gene expression regulators that could be used as therapeutics, however, there is a lack of knowledge on the functions and methods for their delivery into inflamed tissues. The first aim of this project is to clarify the role of miR-146 family in inflammasome activation and airway inflammation in mouse models. The second task is to select and characterize novel miRNAs associated with tissue-specific immune responses in AD, Ps and asthma. The third aim is to optimize the cell penetrating peptide-based miRNA delivery in mouse models of skin and airway inflammation. The project provides deeper knowledge on the pathogenesis of chronic inflammatory diseases and advances miRNA delivery methods to target these disorders.

 

Project: Center of Excellence for Genomics and Translational Medicine (Archimedes Foundation, SMVBS16142T)
Period: 01.01.2016−01.03.2023
Contact: Professor Ana Rebane
E-mail: ana.rebane@ut.ee

The CoE for Genomics and Translational Medicine aims to translate discoveries in the field of genomics into improved understanding of molecular mechanisms of disease. The new interdisciplinary environment of the CoE makes it possible to interpret and rapidly utilize data produced by cutting edge omics technologies. The Centre will explore genetic and biolological mechanisms of disease by 1) investigating DNA sequence variants that contribute to disease through large scale genomic screens, and 2) using molecular and cellular bology techniques complemented by the use of animal models to study their role in disease. This offers an exciting platform for discovering important biological mechanisms that contribute to disease. The outputs of the project are anticipated to unravel processes underlying complex disease, identify new therapeutic targets and enable development of new approaches for disease prevention and precision medicine that will have a major impact in Europe and globally.

 

Project: Biomarkers in Atopic Dermatitis and Psoriasis (European Commission, Horizon2020, MMVBS19122)
Period: 01.04.2019−31.03.2024
Contact: Professor Ana Rebane  
E-mail: ana.rebane@ut.ee

Our objective is to provide a taxonomic and predictive systems medicine model of Atopic Dermatitis and Psoriasis based on clinical and molecular profiling to (i) identify determinants of clinically relevant outcomes (disease manifestation, progression, comorbidity development and treatment response) (ii) improve understanding on shared and distinct disease mechanism(s) and associated signatures, and their relative importance in patient subpopulations and (iii) deliver biomarkers that identify disease trajectories and treatment response for use in drug development and clinical practice. BIOMAP will create a biospecimen and data resource of unprecedented scale and depth, accessible via a central data and analysis portal,
harmonizing diverse, high quality, multi-dimensional datasets on skin and blood (whole and single cell), large scale population-based and trial data; parallel clinical research infrastructure will deliver supplementary material flexible to the needs of the consortium. This resource will be systematically analyzed using state-of-the-art methodologies in epidemiology, molecular profiling, skin biology and mathematical modelling to define disease and drug endotypes and how these interact with lifestyle and environmental factors. Selected, highly discriminatory, associated biomarkers will pass through a
diagnostics pipeline (novel in-silico trial methods and assay development), ready for immediate translation. BIOMAP is expected to drive drug discovery to target causal mechanisms, shorten drug development pathways, and fundamentally change the diagnosis and management paradigm, from re-active to pro-active strategies that encompass disease biology and life-time trajectory, matching the intervention (prevention, modification of risk factors, therapeutics) with endotypes. Clinically annotated endotypes and associated biomarkers will identify when, in whom and how to intervene to minimize
disease impact and improve outcomes.

 

Project: The role of microRNAs in the regulation of the generation and maintenance of skin resident memory T cells (Estonian Research Council, GMVBS22028J)
Period: 01.01.2022−31.12.2023
Contact: Research Fellow Helen Vaher 
E-mail: helen.vaher@ut.ee

Allergic contact dermatitis (ACD) is an inflammatory skin condition that is characterized by dry, scaly, and itchy skin. An important part of the immune response to contact allergens is local memory, which is mediated through specialized cells called resident memory T (TRM) cells. MicroRNAs (miRNAs) are short RNA molecules that regulate the expression of a large number of genes on a post-transcriptional level. The general aim of this project is to clarify what miRNAs are important for the generation and maintenance of epidermal TRM cells in a mouse model of ACD and patients with ACD. Additionally, we will analyze how these miRNAs themselves are regulated in cells. The current project will expand the knowledge of miRNA expression in ACD and thereby lead to a better understanding of molecular mechanisms that contribute to the development of ACD.

 

Read more about the research of the Chair of Human Genetics.

 

Project: Mono- and digenic causes of male infertility in the exome sequencing era: novel genes, digenic inheritance, pleiotropic effects and clinical implications (Estonian Research Council, GMVBS21064PR)
Period: 01.01.202131.12.2025
Contact: Professor Maris Laan 
E-mail: maris.laan@ut.ee

Although infertility affects ~7% of men, currently 60% of cases remain unexplained. This interdisciplinary research project is expected to identify novel genetic causes for impaired testicular development resulting in severe spermatogenic failure and/or genital dysgenesis. The study will significantly improve the knowledge of genetic heterogeneity behind the same clinical diagnosis, male and female phenotypic spectrum in carriers of the same mutation, and bring novel insights into the development and function of reproductive organs. The study data will serve for improved diagnostics, prognostics, management decisions and genetic counselling of infertility and men’s general health. Uncovering genetic defects behind extreme phenotypes of male infertility is highly valuable to understand the aetiology and molecular pathways that in turn will promote clinical research, including development of novel and preferentially non-invasive treatment targets and options for spermatogenic impairment..

 

Project: Maternal serum based multimarker test for the risk assessment to develop preeclampsia: translation to the clinic (ESTPRE study) (Estonian Research Council, SMVBS22077)
Period: 01.03.202228.02.2023
Contact: professor Maris Laan 
E-mail: maris.laan@ut.ee

Preeclampsia (PE) is a pregnancy complication that is accompanied by sudden increase in maternal blood pressure and dysfunction of several organs. We have developed a maternal serum based multimarker 6PLEX test for PE prognosis with high specificity and sensitivity. In this project, we aim to test its performance and added value in PE risk assessment in routine clinical practice in three Estonian clinics. The project is expected to improve the accuracy of I trimester PE prognosis formula, develop the pipeline for routine test usage and its straightforward clinical application. The developed test is expected to have a wide impact in the society as it contributes to the quality of personalized healthcare in reproductive medicine and lowers the PE-related health risks of the mother and newborn, and respective management costs. Commercialization is foreseen through patenting and licensing; University of Tartu has filed two patent applications related to this innovation.

 

Read more about the research of the Department of Immunology.

 

Project: Immune mechanisms in adulthood diabetes (Estonian Research Council, GMVBS0377PR)
Period: 01.01.2020–31.12.2024
Contact: Professor Raivo Uibo  
E-mail: raivo.uibo@ut.ee

Central immune tolerance of T cells is established in the thymus. An important factor in the thymic immune tolerance is autoimmune regulator (AIRE) that in thymic medullary epithelium promotes the selection of developing T cells. During recent years, many key findings have advanced our understanding how the immune tolerance to self-antigens is achieved. Nevertheless, several mechanistic aspects of the central tolerance have remained enigmatic. In this proposal, we will study the role of Aire and thymic medullary epithelium in promiscuous self-antigen expression; the homeostatic regulators in the thymus function and the anti-cytokine autoantibodies developed by human patients with AIRE mutations. Our research will provide new insights into the tolerance mechanisms, with a particular relevance to the understanding how autoimmune attack to body tissues is avoided, but also has a potential in development of therapeutic monoclonal antibodies.

 

Project: Human Exposomic Determinants of Immune Mediated Diseases (European Commission Horizon2020, MMVBS20017R)
Period: 01.01.2020–31.12.2024
Contact: professor Raivo Uibo  
E-mail: raivo.uibo@ut.ee

Immune-mediated diseases (IMDs) are increasing rapidly in the developed countries constituting a huge medical, economic and societal challenge. The reasons to this epidemic are not known, but exposome needs to play an important role since
genetic factors cannot explain such a rapid change. In the HEDIMED project altogether 20 academic and industrial partners will join their multidisciplinary and supplementary forces to identify exposomic determinants which are driving this epidemic.
The project is based on a combination of data and biological samples from large clinical cohorts constituting the largest clinical resource in this field including 350.000 pregnant women, 28.000 children prospectively followed from birth and 6.600
children from cross-sectional studies. HEDIMED focuses on common chronic IMDs that cause a significant disease burden, including type 1 diabetes, celiac disease, allergies and asthma. Exposomic disease determinants and the underlying biological pathways will be identified by exploratory approach using advanced omics and multiplex technologies combined with cutting–edge datamining technologies. Particular emphasis is paid on early fetal and childhood exposome since the disease process is known to start early. Inclusion of several IMDs makes it possible to identify determinants that are common for many IMDs facilitating the development of widely operating treatments. HEDIMED includes also data and samples from clinical trials that have used exposomice interventions and cell and organ culture models to help the identification of causal associations. HEDIMED will generate an open-access toolbox that offers various kind of data, new
technologies, interactions forums, latest information and functional tools for several stakeholders to facilitate the efforts to find ways to control the IMD epidemic. HEDIMED will generate several innovations which can become exploited widely in
diagnostic, therapeutic, preventive and health-economical applications. This project belongs with other 8 projects to European Exposome Cluster.

 

Read more about the research of the Department of Pathophysiology.

 

Project: Integrated model for personalized diabetic retinopathy screening and monitoring using risk-stratification and automated AI-based fundus image analysis (State Education Development Agency (SEDA), MMVBS21381)
Period: 01.05.2021–30.04.2024 
Contact: professor Vallo Volke  
E-mail: vallo.volke@ut.ee

Diabetic retinopathy (DR) is the leading cause of blindness and reduced vision in the developed world. Many countries in Europe, including Latvia, Estonia and Lithuania, have no national screening programs for DR, while Norway – recently, has implemented such programs, which are not yet personalized. Currently, the monitoring interval for patients with DR is set according to guidelines is “rigid”. It may, however, vary from patient to patient, as it depends on various risk factors. The cost of regular annual screening of DR is enormous, while the rising number of patients with diabetes mellitus (DM) surpasses the capacity of ophthalmologists. The aim of the project is to implement a new personalized DR screening and monitoring program using artificial intelligence (AI) for future applications in the integrated care of patients with DM.
Objectives of this project include: 1. Evaluation the current DR status and risk factors in patients with DM in each partner country. 2. Improvement and implementation of a personalized risk-stratification algorithm in the daily diabetes eye screening.
3. Utilization of fast data extraction methods from medical electronic records and AI to detect novel risk parameters for DR. 4. Evaluation of the cost-efficacy of running an AI -based DR screening and monitoring program in the partner countries. 5. Initiation of a sustainable screening and monitoring programs for DR in the partner countries as part of their ongoing or future eHealth initiatives.
The project will be promoted by University of Latvia (Riga, Latvia). Other participants will be Tartu University (Estonia), Oslo University hospital (Oslo, Norway) and Lithuanian University of Health Sciences (Kaunas, Lithuania).

 

Project: Staining study to – differentiate organelle originated EV´s from other nanoparticles – via f-NTA (Particle Metrix QUATT) (Particle Metrics GbmH, VMVBS21611)
Period: 28.10.2021–31.08.2023 
Contact: Professor Alireza Fazeli
E-mail: alireza.fazeli@ut.ee

Our project aims to use fluorescent organelle-specific dyes in combination with NTA, for the characterization of EV heterogenei§ in a given sample.

 

Read more about the research of the Department of Microbiology.

 

Project: conect4children- COllaborative Network for European Clinical Trials For Children (European Commission Horizon2020, MMVBS18106R)
Period: 01.05.2018–30.04.2024
Contact: Professor Irja Lutsar
E-mail: irja.lutsar@ut.ee

The main objective of the COllaborative Network for European Clinical Trials For Children (conect4children, c4c) is the development, implementation and evaluation of robust, sustainable and integrated pan-European network for trial delivery to enhance, support and optimise paediatric drug development.
The ambition of the c4c consortium is to provide an integrated platform for the efficient and swift delivery of high quality clinical trials in children and young people across all conditions and phases of the drug development process. c4c aims to bring innovative processes to all stages of clinical development by generating a new model of:
1. organization: this infrastructure, emphasizing inclusiveness and collaboration across geography, specialty, sectoral (industry/non-industry) and cultural or societal backgrounds, has no equal in the current fragmented European clinical research environment;
2. clinical development processes: best practices and up-to-date expert advice will be consolidated to inform
approaches and methods and identify gaps to be addressed by c4c to increase the overall efficiency, with methods tested and subsequently refined in the context of validation trials.

 

Project: GLP1 receptor agonist Liraglutide and NRF2 activator RTA-408 therapy to relieve neurodegenerative symptoms in rat model of Wolfram syndrome (Estonian Research Council, GMVBS20066PS)
Period: 01.01.2020–31.12.2023 
Contact: Associate Professor Mario Plaas
E-mail: mario.plaas@ut.ee

 

Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disorder which is caused by mutations in the WFS1 gene. First symptoms are diabetes mellitus, followed by optic nerve atrophy, deafness and neurodegeneration. Recently, we have demonstrated that early treatment with GLP-1 receptor (GLPr) agonist liraglutide decreases ER stress, inflammation in Langerhans islets and thereby delays the development of diabetic phenotype in Wfs1 deficient rats. Today, first WS patients are treated with GLP1r agonist and there is a clear antidiabetic protective effect. However, the neuroprotective effects of this drug are still unknown. Recently, we have found another promising drug against WS (RTA-408); this drug is in phase 3 trials in Friedreich ataxia patients, where it has shown neuroprotection. The aim of this project is to evaluate the neuroprotective effects of liraglutide and RTA-408 using a rat model of WS. The results of this study will be directly translatable to human practice.

 

Project: Developing treatment options and gene therapy protocols to treat Wolfram Syndrome using Wolfram syndrome rats (Eye Hope Foundation, MMVBS21231)
Period: 01.01.2021–31.12.2022
Contact: Associate Professor Mario Plaas
E-mail: mario.plaas@ut.ee

We propose to study novel therapeutic strategies in the Wfs1-rat model of Wolfram Syndrome (WS) by two complementary approaches, both aiming to prevent cellular degeneration. First, we will elucidate the role of Wfs1 on RAAS and Bradykinin pathways and we treat the animals with RAAS modulators (GLP1/GIP receptor co-agonist, Valproate and a few direct RAAS modulators), to study how these treatments modulate the function of RAAS system and WS progression. Complex phenotypic tests and morphological analyses will be performed to assess the outcome treatment and detect possible side effects.
Secondly, we will develop lentiviral and adeno-associated virus vectors expressing wildtype WFS1. After successful tests in vitro we will continue with animal experiments to validate virus vector expression patterns and virus vector doses. 

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Doctoral defence: Marilin Ivask “Transcriptomic and metabolic changes in the WFS1-deficient mouse model”

On 29 Novembril at 15:00 Marilin Ivask will defend her doctoral thesis „Transcriptomic and metabolic changes in the WFS1-deficient mouse model“.
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Seminar by Prof Gregory Lavieu

Seminar by Professor Gregory Lavieu