Open projects at Biotech Research and Innovation Centre

• https://www.genomedatalab.org/ ; https://www.bric.ku.dk/research-groups/Research/supek-group/
• We study human genomes using statistics and AI, with a focus on evolution of cancer cells. Particular interests involve understanding of DNA repair organization across human chromosomes, and the interplay with chromatin remodelling.

• https://orbit.dtu.dk/en/persons/ole-lund ; https://www.healthtech.dtu.dk/
• Immunology and microbiology: epitope, whole-genome sequencing, antimicrobial resistance, infectious agent; Biochemistry and genetics: major histocompatibility complex, allele, T-cell, antibiotic resistance

• What?
  • We want to develop interpretable machine learning linking DNA with RNA/epigenomics, applied to understanding biological mechanisms behind DNA indels and structural variants (rearrangements) that cause cancer by promoting local chromatin or gene activity changes.
• How?
  • (i) Design interpretable neural networks for genomic data; (ii) Integrate multiple data types (indels, structural variants, expression, chromatin, clinical); (iii) Develop analysis and/or visualization tools for regulatory mechanisms.
• Why?
  • Biological impacts include a map of regulatory variant effects in tumors, new oncogene activation mechanisms; Better understanding of enhancer hijacking, and highlighting novel therapeutic targets. Technical impacts include a novel interpretable AI architecture; Tools for visualizing regulatory changes; and a multi-modal data integration framework

• This project will uniquely bridge expertise from two labs at BRIC/KU and DTU to create interdiscplinary synergy between genomics and applied AI research.
• Cancer Genomics Application (Supek expertise): (i) Analysis of indel and/or structural variant patterns; (ii) Enhancer/promoter disruption mechanisms; (iii) Oncogene activation or TSG inactivation patterns; (iv) Integration with epigenomic or spatial signatures.
• Clinical Integration and Intepretation (Lund expertise): (i) Translation to decision support via training ML models; (ii) Integration of patient outcomes into training data; (iii) Multi-modal data integration.

• https://www.genomedatalab.org/ ; https://www.bric.ku.dk/research-groups/Research/supek-group/
• We study human genomes using statistics and AI, with a focus on evolution of cancer cells. Particular interests involve understanding of DNA repair, as well as applying AI to genetic data for the purposes of having interpretable predictive modes. Other interests involve automated inference of gene function from text and genomes (cancers, human populations, bacterial genomes) using AI.

• https://researchprofiles.ku.dk/en/persons/jesper-bruun
• Jesper does research in learning, teaching and education in the Sciences with a focus on Physics; primarily in upper-secondary and university education. He is particularly interested in the use of digital and other technologies in teaching and in a broader educational context. Recently, he has become interested in Learning Analytics and how we as researchers can use big data to understand and improve our educational system across education levels.

• What?
  • We want to a build LLM-based system for gamification of scientific literature, to promote learning and research by graduate and undergraduate students. Reading papers should become fun and engaging, and we will employ generative AI to make cutting-edge literature more accessible to junior experts in training.  We will apply this generative AI to scientific texts in genomics. Concurrent with the development of generative AI for enaging with literature, we will investigate how students use the developed tools and what they gain from that use.
• How?
  • Two methdologies will be developed to harness LMMs (e.g. Llama-3, Claude, GPT or similar) to reframe and gamify reading and understanding of scientific literature, and implemented into tools. First tool, the “AI lens” will rephrase any chosen papers to improve clarity and remove jargon, while being tailored to the knowledge level of each individual reader. Second tool, the “AI alchemy” will auto-generate a simple yet engaging game from every scientific paper, with the goal of gamifying learning by building connections between concepts relevant to a field. The investigation of student use of AI lens and AI Alchemy will be carried out via collecting logs of student interactions with the tools, video recordings of students using the tool, and interviews to uncover student perceptions of and reasonings about their use and benefits of using the tools. The analysis of these data will involve state of the art network analytical methods developed in Physics Education Research.
• Why?
  • Scientific publications are ever-increasing in complexity and size, and this trend is unlikely to change. Therefore keeping up with the research literature in a given field is a formidable challenge for scientists-in-training (MSc students, PhD student) and also, increasingly so, for more senior researchers. AI tools to help parse science and make it more accessible while, importantly, retaining rigor, will likely be very beneficial to promoting training of junior scientists and thus for progress of science as an enterprise. However, little is known in the literature about how students percieve specialised tools nor about the realised learning potentials of such tools.

• This project will bridge expertise from three labs, one at the Biotech Research and Innovation Centre (BRIC), and two at Department of Science Education at KU (Center for Digital Education, and KU Physics Education Research group), to generate a uniquely interdiscplinary project bridging genomics, AI and paedagogical sciences.
• The Supek group will contribute expertise in Human Genomics, in applied AI and in software tool development. The CDE and KUPER groups will contribute expertise in analytical and methodological methods from Physics Education Research and in AI in science teaching and learning.
• PhD candidates of diverse educational backgrounds are encouraged to apply. We value having good computing skills, in particular being able to code at least an intermediate level in one programming language.  Moreover, an interest in life sciences and genomics in specific is a plus (but a formal eduction in life sciences is not required!)

• https://www.bric.ku.dk/research-groups/Research/kristensen-group/ 
• Glioblastoma is the most frequent and malignant type of brain cancer with poor survival outcomes for most patients. Novel therapeutic targets and strategies that overcome the efficient mechanisms of resistance are urgently needed. Our aim is to identify novel targets and to understand and overcome mechanisms of resistance in the microenvironment of glioblastomas. This is obtained by patient tissue and model systems combined with spatial transcriptomics and bioinformatics. We would like to recruit for the bioinformatics part.

• https://nbi.ku.dk/english/research/biocomplexity/uni-bio-lab/
• The group is interested in how populations of cells self-organize to achieve complex behaviours. One direction in our group is on understanding inter- and intra-cellular coordination to respond to stresses (unfolded proteins, reactive oxygen species, antibiotics, inflammation). Another is how complex forms and shapes emerge during development of organs and organoids.

• What?
  • We interrogate the spatial cellular organization of cells in glioblastoma. This includes (1) the tumor core, (2) the transition zone where the cancer cells start infiltrating the brain and (3) the outer regions where cancer cells have infiltrated into the brain. We focus on the interactions between tumor cells and the microenvironment. The microenvironment is heterogenous leading to potentially different mechanisms of resistance. Adding to the complexity, there is a high frequency of non-tumor cells in glioblastomas leading to potential critical cross-talk between tumor cells and microglia/macrophages and other cell types.
• How?
  • We use spatial profiling to investigate the spatial organization of patient brain cancer tissue as well as tissue and cells in in vitro and in vivo patient-derived brain cancer models. We have existing spatial data sets and we are currently generating novel comprehensive datasets (see paper example from Kristensen group: https://pubmed.ncbi.nlm.nih.gov/39251578/). To gain quantitative understanding of the cancer infiltration and resistance, we will develop data-informed hybrid models, where discrete agent-based approaches will model individual cell behavior and continuous differential equations will simulate intercellular signaling dynamics (see paper example from Trusina group: https://pubmed.ncbi.nlm.nih.gov/36681690/) 
• Why?
  • Understanding the spatial organization of glioblastoma and thereby the heterogeneity and identity of individual cell is critical in order to develop novel successful therapies.

The interdisciplinary aspects will cover mathematical and biophysical modelling of inter-cellular regulatory networks, cell-cell interactions covering also tumor cell proliferation and tumor cell infiltration into brain tissue, which are hallmarks of brain cancer. We will be striving towards spatial data-informed models, that will increase our understanding of how we can target e.g. tumor cell proliferation and infiltration more efficiently. We envision that the models and simulations developed will guide future experimental studies by generating new questions and hypotheses.

• bric.ku.dk/research-groups/Research/andersen-group/
• The Andersen group utilizes genome-wide approaches in modeling liver and bile duct cancers, stratifying patients for advancing diagnostic and prognostic biomarkers, and novel therapeutic options. Our research is focused into 3 main project themes: i) Immunogenomics, ii) metabolism, and iii) epigenomic remodeling. The outcome of our research is to significantly guide novel treatment modalities and impact the clinic to improve patients’ outcomes.

• kemi.dtu.dk/mhc/
• The Clausen research group has a special interest in chemical biology, i.e. using synthetic chemistry to provide tool compounds for answering biological questions. This overall research theme currently includes HTS and FBDD against protein and RNA targets, medicinal chemistry related to oncology, inflammatory and infectious diseases, prodrug design and synthesis, vaccine development, plant polysaccharides, and new materials from plant cell wall components.

• What?
  • Bile duct cancers arise from the epithelium lining the biliary ducts. Although these tumors are relatively rare, the incidence rate has increased globally over the last three decades and expected to rise another 400% in the next decade. The reason for this increasing secular trend remains unclear. In a recent project, we have proposed a new molecular-driven bile duct cancer taxonomy, stratifying intrahepatic tumors based on somatic perturbation mechanisms defined by mutational, structural, epi-mutational, therapeutic, and clinically distinct pathology (see Nepal & O’Rourke et al. Hepatology, 2018). Half of these patients remain elusive lacking mutations in key driver genes. However, these tumors show significant enrichment in various epigenetic processes and chromatin remodeling. As a follow-up to this study, the Andersen group has identified a novel member and methyltransferase-like protein and its protein interactor. This protein interaction  involves the activating signal cointegrator-2 (ASC-2)-containing complex (ASCOM) complex and regulation of its role in histone 3 lysine 4 (H3K4) methylation. Regulation or moreso deregulation (at the tumor state) of histone methylation impacts broadly transcriptional programs and cellular processes.

We are offering a bright and engaged PhD student an ambitious project as part of the INTERACT COFUND PhD Program that involves undertaking the challenge to develop an inhibitor targeting this novel protein-protein interaction.

• How?
  • If you undertake this challenging project, you will have a unique supervisor team. You will have access to detailed knowledge about human biology (disease focused) and informatics (Andersen group, BRIC) and screening and medicinal chemistry (MHC group, DTU). We have developed bile duct cancer and normal cells, which are genetically-modified (knock out (KO) and overexpression (OE)) of this gene representing the methyltransferase. These models are well-characterized in vitro (biochemically and molecular), genomically (RNA- and ChIPseq), and in vivo (xenograft modeling). Using these cell models, we are offering a student to work on medicial chemisitry, assay development, automatisation, and highthroughput screening of lead-like compound(s). The aim is to identify hits that can form the basis of design and development of inhibitor(s) for futher testing in vitro and in vivo.  

• Why?
  • If you undertake this collaborative project, you will be part of a team that will develop the first lead compound targeting this complex and inhibiting the protein-protein interaction. This will be the first steps of developing a potential novel cancer drug. The interplay of disease biology and small molecule discovery is a unique feature of this project.

If you undertake this collaborative project, you will take part in a team not only crossing to different research group within two very different fields. You will also have a leg at two different universities – Department of Health and Medical Science, University of Copenhagen and Department of Chemistry, Technical University of Denmark. As such, the interdisciplinary aspects of this PhD project rest on the collaboration between the Andersen group (BRIC) and MHC group (DTU). The project involves aspects on human cell biology (molecular biology, genomics, and bioinformatics) and medicinal chemistry (screening, chemical biology, and synthesis). The work-flow will integrate knowledge of cell and disease biology with capacities for high-throughput screening for modulators of protein-protein interactions. As part of an iterative workflow, primary screening (based on viability of a relevant cell line) will be followed by counter-screening (using precision epigenetic models) to determine which initial hits are affecting the specific histone methylation state in a disease-relevant fashion – and these hits will be prioritized for follow-up hit-to-lead development.

• https://www.bric.ku.dk/research-groups/Research/Sorensen_Group/
• The objectives of our lab are to study how cells maintain genome stability to avert cancer and genetic disorders, accurately assess the functional consequences of mutations, and investigate potential therapeutic avenues created by specific mutations.

• https://www.dtu.dk/english/person/katrine-qvortrup?id=54449&entity=profile 
• We use small organic molecules to approach a wide variety of challenges in the field. Current focus is directed against cancer, inflammatory disease, drug delivery and plant cell wall biology and biotechnology. Research efforts are aimed at the development of screening technology, new chemical probes, diagnostic tools, and lead compounds for drug discovery.

• How?
  • We will develop approaches for site-directed intracellular phosphorylation of proteins in mammalian cell culture systems via collaboration between Sørensen and Qvortrup teams.
• Why?
  • Phosphorylation is a crucial post-translational modification of proteins. However, templated protein phosphorylation inside mammalian cells has never been done before, accordingly, we cannot know with certainty if any intracellular phosphorylation is biologically crucial as we cannot model it. This is a problem for  many research areas, we will address cell cycle control pathways that are biologically important and cancer therapy targets. We are on the way to develop testable approaches to address the problem.

We will jointly develop systems that allow regulated intracellular phosphorylation of biologically critical phospho-sites. Sørensen team research will be focused on developing kinase targets and phenotype analysis in cells. A  system for regulated, targeted protein phosphorylation will be co-developed with the Qvortrup team, who supervises regarding the intellectual aspects of creating the system. Qvortrup team will also provide relevant molecular probes needed to carry out the phosphorylation reaction. The student will be based in the Sørensen team conducting the project with bimonthly online meetings with the Qvortrup team. A stay of up to 6 weeks in the Qvortrup team is also planned.

• https://www.bric.ku.dk/research-groups/Research/Sorensen_Group/
• The objectives of our lab are to study how cells maintain genome stability to avert cancer and genetic disorders, accurately assess the functional consequences of mutations, and investigate potential therapeutic avenues created by specific mutations.

• https://www.dtu.dk/english/person/katrine-qvortrup?id=54449&entity=profile 
• We use small organic molecules to approach a wide variety of challenges in the field. Current focus is directed against cancer, inflammatory disease, drug delivery and plant cell wall biology and biotechnology. Research efforts are aimed at the development of screening technology, new chemical probes, diagnostic tools, and lead compounds for drug discovery.

• How?
  • We will base this project on new means to analyze DNA nuclease functions by developing cell-based enzyme activity assays.
• Why?
  • We need to detect and track DNA nuclease activities in human cells as these are main drivers of mutagenesis and therapy resistance. More specifically, we focus on the Caspase-activated DNase (CAD) that drives several types of resistance. To this end, we will develop cell-based reporter assays that will allow precision measurements of nuclease activities, which will be used to study nuclease mechanisms as well as development of nuclease inhibitors with potential usage in anti-cancer therapy.

We will jointly develop systems to monitor intracellular DNA nuclease activities. The Sørensen team will focus on specific nucleases (especially CAD), setting up the cellular systems, and conducting the cell-based phenotype analysis. The Qvortrup team will supervise regarding development of reporter systems to monitor nuclease activities. 4 different assay concepts will be explored in prioritized order.  The student will be based in the Sørensen team conducting the project with bimonthly online meetings with the Qvortrup team. A stay of up to 6 weeks in the Qvortrup team is also planned.  

• https://www.bric.ku.dk/research-groups/Research/Porse_Group/
• We focus our research on elucidating mechanisms governing normal and malignant haematopoiesis with special emphasis on the behaviour of hematopoietic stem cells (HSCs) during adult haematopoiesis and leukemic stem cells (LSCs) in acute myeloid leukaemia. To this end, we employ mouse models of human AML, mouse knockout lines of putative HSC/LSC regulators, primary patient material and a broad range of genome-wide approaches and single cell analyses incl. cutting edge single cell proteomics.

• https://www.bioengineering.dtu.dk/research/research-sections/section-for-medical-biotechnology/cell-diversity-lab
• Our mission in the Cell Diversity Lab is to unravel fundamental biological concepts controlling heterogeneity within complex biological systems, especially those of the blood system and cancer. We aim to use our leading position in the field of scp-MS to identify druggable signalling mechanisms that will advance therapy and diagnostics for patients suffering from complex diseases. By computationally integrating several experimental approaches such as Mass Spectrometry (MS), Next-Generation Sequencing, FACS sorting and in vivo xenograft models, we aim to gain a better understanding of cellular signal processing at the single cell level.

• What?
  • The project aims at understanding how ribosomopathies, a collection of human conditions that affect ribosome function, impact on the human proteome at single cell level
• How?
  • We will use single cell proteomics by mass spectrometry (scp-MS) to measure protein levels in individual cells using material from patients suffering from ribosomopathies. We will focus on erythroid differentiation as one of the main features of these conditions is anaemia. We will also establish CRISPR-KO and/or knock-in models of normal hematopoietic stem and progenitor cells (HSPCs) and subject these (and relevant controls) to erythroid differentiation followed by scp-MS measurements. The latter will be supplemented by scRNA-seq experiments which will be integrated with the scp-MS modality, allowing us to perform mathematical modelling to characterize the impact of ribosomopathy-associated lesions on RNA/protein relevant rate constants.
• Why?
  • While transcriptome analysis has revolutionized biological understanding, ribosomopathies impact specifically on protein synthesis and are therefore poorly characterized by this transcriptome analyses. Through the use of scp-MS, it is our ambition to gain insights into how ribosomopathies impact on the proteome which may identify targets for future intervention strategies.

The project will combine experimental haematology, state-of-the-art gene editing approaches with single cell transcriptome and proteome analysis on primary human patient material. Finally, the project will also involve high-end computational analyses to integrate and model the multimodal datasets.

• https://www.bric.ku.dk/research-groups/Research/duxin-group/

The Duxin team studies the essential processes involved in maintaining genome integrity. Specifically, the team is interested in understanding how cytotoxic DNA lesions known as DNA-protein crosslinks (DPCs) are tolerated by cells and cleared from the genome. These lesions are generated by mainstream chemotherapeutics (e.g. topoisomerase poisons) but are also the common byproduct of cellular metabolism (e.g. formaldehyde).

• https://nbi.ku.dk/english/research/biocomplexity/center-for-optical-bio-manipulation-cobm/

Poul Martin Bendix is an associate professor in Biophysics and is leading the Experimental Biophysics lab at the Niels Bohr Institute. His main research interests include biophysics and dynamics of cell surface structures and associated proteins. He is leading the center of Optical Bio-Manipulation, which is currently hosting a number of interdisciplinary single molecule projects investigating protein-DNA interactions using the most advanced C-Trap system  (Optical tweezers) currently available. 

• What?
  • We are seeking a motivated PhD student with a keen interest in the mechanisms that maintain genome integrity and underly the cytotoxicity and resistance of chemotherapeutics. Particularly, this project aims to understand how the DNA repair factor PARP1 recognizes and senses Topoisomerase 1-DNA lesions induced by the mainstream chemotherapeutic topotecan.
  • Inhibitors of topoisomerase 1 (TOP1)—an enzyme that resolves topological stress during DNA replication and transcription—have been widely used in the clinic since 1994 to treat ovarian, lung and colorectal cancers, as well as leukemia (Bjornsti and Kaufmann 2019). TOP1 poisons such as topotecan, function by covalently trapping TOP1 cleavage complexes (TOP1ccs) on DNA (Pommier et al. 2022). TOP1ccs contain a single-strand break that can become a toxic double-strand break (DSB) if the replication machinery encounters the break and ‘collapses’. To prevent this, cells have evolved a sophisticated pathway for the rapid detection and resolution of TOP1ccs.
  •  We  recently identified that the DNA repair factor PARP1 is specialized in sensing and targeting TOP1ccs for repair (Fábián et al. 2024). This pathway is conserved in vertebrates, and can explain the synergistic toxicity between TOP1 and PARP1 inhibitors (Kinneer et al. 2023). To guide the development of improved approaches for using these inhibitors, we aim to visualize and thereby decipher the mechanisms that link PARP1 sensing to TOP1cc removal.
  •  This project will combine the expertise of the Duxin and Bendix groups, utilizing the biochemical system of Xenopus egg extracts and single-molecule imaging via optical tweezers. Specifically, we plan to generate a long DNA molecule containing a fluorescently labeled, site-specific TOP1cc and observe its resolution by PARP1 using both Xenopus egg extracts and purified proteins. This work will pave the way for a greater understanding of how genome stability is maintained during healthy development and aging, and how manipulating these mechanisms could advance therapeutic interventions.
• How? (Methodological approaches and used technologies)
  • The Duxin group takes advantage of a protein extract system derived from eggs from African clawed frogs (Xenopus laevis). These protein extracts have the remarkable capacity to reiterate processes of DNA replication and DNA repair in a cell-free environment, providing a unique opportunity to delineate the molecular mechanisms underlying complex DNA transactions. Notably, these extracts effectively recapitulate TOP1cc repair via PARP1.
  • Pól Martin Bendix is a biophysicist specialized in the study of macromolecular interactions. He was recently awarded an infrastructure grant to acquire and install one of the most sophisticated C-trap optical tweezers/fluorescent system (Lumicks). This system enables the direct visualization (confocal/STED) of DNA molecules containing fluorescently labelled site-specific lesions.

• Why? (Why is this interesting/important)
  • Understanding how PARP1 scans and detects TOP1ccs is a fundamental question underyling the cytotoxic combination effect of PARP and TOP1 inihibitors. If we can undertand how PARP1 can detect a TOP1cc, we will be able to develop better drugs to specifically target PARP1’s role in TOP1cc repair.

References

Bjornsti, Mary-Ann, and Scott H. Kaufmann. 2019. “Topoisomerases and Cancer Chemotherapy: Recent Advances and Unanswered Questions.” F1000Research 8 (September): 1704.

Fábián, Zita, Ellen S. Kakulidis, Ivo A. Hendriks, Ulrike Kühbacher, Nicolai B. Larsen, Marta Oliva-Santiago, Junhui Wang, et al. 2024. “PARP1-Dependent DNA-Protein Crosslink Repair.” Nature Communications 15 (1): 6641.

Kinneer, Krista, Philipp Wortmann, Zachary A. Cooper, Niall J. Dickinson, Luke Masterson, Thais Cailleau, Ian Hutchinson, et al. 2023. “Design and Preclinical Evaluation of a Novel B7-H4-Directed Antibody-Drug Conjugate, AZD8205, Alone and in Combination with the PARP1-Selective Inhibitor AZD5305.” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. American Association for Cancer Research (AACR).

Pommier, Yves, André Nussenzweig, Shunichi Takeda, and Caroline Austin. 2022. “Human Topoisomerases and Their Roles in Genome Stability and Organization.” Nature Reviews. Molecular Cell Biology 23 (6): 407–27.

We aim to combine the unique expertises in DPC repair from the Duxin lab and single molecule protein-DNA visualization from the Bendix lab to determine how PARP1 scans DNA and identifies TOP1ccs. By leading this project, the PhD student will gain extensive experience in molecular biology and biochemistry using Xenopus egg extracts (Duxin lab), as well as in biophysics through fluorescent microscopy and single-molecule studies (Bendix lab).

• https://bric.ku.dk/people/issazadeh_group/?pure=en/persons/326048
• Our vision is to determine the function of shared genes between central nervous system (CNS) neurons and immune cells, disruptions in which often lead to neurodegenerative diseases of the CNS with inflammatory components. Our research team focuses on the signaling pathways that maintain CNS homeostasis, which is central for preventing neuroinflammation and neurodegeneration. The aim of the current project would be to utilize unbiased multi-OMICs of brain and immune system and integrate the independent OMICs to reach higher level of data mining. This requires both understanding of experimental biology but more importantly bioinformatic interest and expertise.

• http://www.healthtech.dtu.dk
• Our vision is to utlize and develop the state-of-the-art bioinformatic analytical tools to analyze and integrate single cell OMICs applied to broad field of biological sciences including but not limitted to:
• T cell immunology
• B cell immunology
• Cancer immunology
• Vaccine efficacy

• What?
  • The goal is to enhance the understanding of how immune-related genes influence the function and biology of neurons and other cells in the central nervous system (CNS). Defects or deficiencies in these immune genes may contribute to neurodegeneration and the associated neuroinflammation.
• How?
  • This will be achieved by leveraging various OMIC datasets and developing new computational and bioinformatics tools to analyze and integrate these datasets. The focus will be on increasing the precision and resolution in identifying novel biological pathways. These findings will then be further explored using gene-editing technologies such as CRISPR/Cas9 for gene knockdowns, gene overexpression, gene-modified mouse models, and other molecular and cellular biology techniques. The ultimate aim is to identify potential therapeutic targets for neurodegenerative diseases.
• Why?
  • Neurodegenerative diseases associated with aging, such as Alzheimer’s and Parkinson’s diseases, are increasingly prevalent in developing societies, imposing significant personal suffering and societal burdens. Despite their high impact, no cures currently exist for these diseases, as their underlying causes remain poorly understood. The aim of this research is to uncover the mechanisms behind these diseases, with the hope of identifying new therapeutic targets for future treatment strategies.

This project integrates neurobiology, neuroimmunology, and computational sciences to achieve its objectives. The host lab has established leading expertise in neuroscience and neuroimmunology, while the co-supervisor has a strong track record in developing and utilizing advanced bioinformatics and computational tools for analyzing OMICs data.

• Website: @BRIC is currently under construction and will be available in January 2025; https://www.stemcellcenter.lu.se/research-groups/bellodi 
• My laboratory explores how prominent RNA modifications, including pseudouridine, regulate gene expression during development and tumorigenesis. A significant interest revolves around the role of pseudouridine-modifying proteins (PUS) in shaping molecular and cellular processes in stem and cancer cells. Using the immune system as a model, my team combines advanced genetics, sequencing, and biochemistry to uncover uncharted epitranscriptomic pathways driving normal and malignant hematopoiesis, aiming to innovate RNA-based cancer therapies.

Associate Professor Sunil Kumar Saini

• https://www.healthtech.dtu.dk/research/research-sections/section-xti/group-t-cell-antigens-and-immunogenicity

Our aim is to discover novel T-cell targets (antigens) and understand the adaptation of T-cells in different disease settings. We perform extensive evaluations of T-cells using cutting-edge technologies we have established over the years. Identification of new T-cell targets and their detailed characterization in cancer, viral infections, and vaccination is key to improving ongoing T-cell therapies and identifying new avenues for therapeutic application.

Associate Professor Junsheng Chen

• https://chem.ku.dk/research_sections/nanochem/jc-group/

We focus on the functions and underlying photophysical properties of fluorescent molecular and semiconductor nanomaterials, with particular interest in their bioimaging applications. We are developing ultrabright fluorescent nanoparticles based on a molecular self-assembly approach. Using ultrafast optical spectroscopy with femtosecond time resolution, we uncover their critical photophysical processes and provide in-depth insights that guide the development of new, high-performance fluorescent nanoparticles.

• What?
  • To delineate how RNA pseudouridylation shapes protein translation, influencing T cell ontogeny and activation under pathophysiological stress conditions, including cancer development.
• How?
  • We will leverage novel conditional knock-out mouse models recently developed in my lab that lack PUS protein, specifically in the T cell compartment. This approach will be complemented by advanced flow cytometric analysis of distinct T-cell populations and cutting-edge techniques to measure protein synthesis at the single-cell level with codon resolution. Furthermore, we will map the pseudouridine epitranscriptome in T cells using innovative sequencing methods, achieving single-nucleotide resolution across various coding and noncoding RNAs, including mRNAs, tRNAs, and tRNA-derived small RNAs.
• Why?
  • Delineating how RNA pseudouridylation adapts protein translation in T cells will shed light on the epitranscriptomic programs that define key transitions during T cell development in the thymus and control mature T cell activation in response to pathogenic cues. These findings will ground-break research in T cell immunity by elucidating new post-transcriptional pathways that drive T cell fate and function in normal and malignant contexts while paving the way for therapeutic strategies targeting the RNA epitranscriptome to boost the anti-cancer immune response.

RNA modifications are emerging regulators of genetic information in health and disease. A striking example is pseudouridine, the most prominent RNA modification in living organisms, with important roles in development and tumorigenesis. My team highlighted an essential contribution of the pseudouridine synthase 7 (PUS7) to protein translation during normal and malignant hematopoiesis. PUS7 deploys novel tRNA-derived small RNAs (tdRs) that repress protein synthesis in hematopoietic stem cells (HSCs). However, how the pseudouridine epitranscriptome adapts gene expression, directing distinct cell fate programs remains mostly unexplored. Based on the premise that protein synthesis is tightly controlled during T cell development and activation, we will combine strong interdisciplinary expertise in RNA, T cell biology, and organic fluorescent nanomaterials to map the epitranscriptomic programs driving T cell identity and activity in vivo. The Chen group has developed organic fluorescent nanoparticles that are over 400 times brighter than conventional fluorescent markers. Here, we will conjugate ultra-bright nanoparticles with single-stranded DNAs to visualize modified RNAs, including mRNAs and tRNAs, to monitor molecular events crucial for T cell maturation and function. This powerful technology will also enable visualization of PUS7-mediated protein synthesis. The Saini group brings expertise in T-cell characterization and in-depth evaluation. The Saini lab has developed state-of-the-art technologies to assess T-cell reactivities in cancer and infectious diseases. We will analyze T-cell phenotypes and antigen-specific functionality impacted by RNA modifiers and tdRs in cancer models and in infectious diseases. Single-cell analysis will help correlate T-cell characteristics affected by RNA modifications with features of T-cells from cancer patients. Dysregulation of RNA pseudouridylation and protein synthesis underlies the etiology of autoimmune disorders and hematological cancers. Hence, knowledge from this project holds great promise for the development of innovative RNA-based therapeutic modulating anti-tumor immunity.