KIRI Postdoctoral Fellows

Name: Andrea del Valle

Project title: Revealing the enteric-sympathetic networks regulating pancreatic secretion

Description: The study investigates using polyphenol-based nanoparticles to target and alleviate oxidative stress in the placenta during pregnancies complicated by Type 1 diabetes (T1D). Despite maintaining glycemic control, pregnancies affected by T1D are associated with risks such as impaired embryo growth, congenital anomalies, and preterm birth due to placental hypoxia and the resulting production of reactive oxygen species (ROS). We synthesized nanoparticles that demonstrated enhanced aqueous dispersibility and stability, confirming their uptake in trophoblast cells. In vitro experiments showed that the nanoparticles reduced exogenous ROS with minimal cytotoxicity. Biodistribution studies in pregnant mice indicated a specific accumulation of nanoparticles in the placenta. Additionally, the study provided insights into the metabolic pathways involved in their placental uptake and metabolism. These findings suggest that using nanoparticles to target the placenta may represent a promising therapeutic approach to managing oxidative stress and improving pregnancy outcomes for women with T1D, addressing the urgent need for safer treatments during pregnancy.

Contact information: andrea.del.valle@ki.se

Name: Cristina Bellotti

Project title: A human-rodent chimeric brain model to study the role of genetics in traumatic brain injury outcome

Description: Traumatic brain injury (TBI) is a major cause of disability and death in adults, yet available treatments are limited. Research in the field heavily relies on the use of animal models of TBI, but positive results are often not replicated in humans. Cerebral organoids (CO) are 3D in vitro models of the human brain which can be developed from human stem cells. COs can be used to model human neuro-pathologies, but several factors limit their use in trauma research. In recent years, it was shown that COs can be transplanted into the brain of rodent hosts, where they can further differentiate and integrate into the neural network. This model offers the unique opportunity to study human brain tissue in the context of a complex living system. The goal of our project is to combine our expertise in organoid development (Sellgren´s lab) and animal models of trauma (Rostami´s group) to establish organoid transplantation as a model to study TBI. In our experiments, we use organoids which contain microglia, the resident immune cells of the brain, to be able to study the immune response to trauma. We transplant the COs into the motor cortex of adult immune-suppressed rats. After CO integration, we use an inhouse model of penetrative TBI and we study the tissue response to injury. The direct comparison between the transplanted CO and the surrounding rat tissue could expose human-specific processes that could be future target for treatment. In successive stages, the model will be used to study the effect of genetic variations on recovery after trauma. Particularly, our focus is on a single-nucleotide polymorphism of the gene codifying the Brain Derived Neurotrophic Factor. 

We will generate organoids from isogenic cell lines differing for the specific SNP and we will study the response to trauma and to candidate drugs.

Contact information: cristina.bellotti@ki.se

Name: Jing Lyu

Project title: Gene-regulatory networks of the early human conceptus

Description: Although it is estimated that 60% of human pregnancies fail in the first 14 days, the underlying reasons are largely unknown. This period of development is largely devoted to establishing the supportive extraembryonic lineages including the amniotic and choroid membranes, the extraembryonic mesenchyme, yolk sack and the placenta. The embryonic epiblast transition from a naive to primed pluripotent state while preparing for gastrulation. For a successful pregnancy, individual cells must sense and respond with exquisite precision to queues from their local environment to form the required cell types and self-organize in a highly regulated and synchronized manner, into early tissue structures. Increased fundamental knowledge of how these cell types are genetically and epigenetically regulated is therefore of utmost importance. However, comprehensive studies of human embryos are still severely limited due to technical and ethical hurdles together with the limited number of donated embryos. Furthermore, embryos are not accessible following implantation in the mother’s womb by the end of the first week. Recent development of stem cell-based embryo models mimicking both pre- and postimplantation stages provides new opportunities that could help to uncover the events that lead to early pregnancy loss. The KIRI postdoctoral fellow will combine the experience of these new embryo models within the Lanner lab with cutting-edge epigenetic profiling technologies at both bulk and single cell level developed by the Elsässer lab to elucidate the gene regulatory networks that control the first two weeks in embryo development.

Contact information: jing.lyu@ki.se

Name: Jingyan He and Karl Annusver

Project title: Unraveling Skin Origins: Developing In Utero Gene Manipulation Tools to Decipher Ectoderm and Mesoderm Contributions to Skin Health and Disease.

Description: Our project aims to trace the ectoderm and mesoderm contribution to skin by using ultrasound-guided in utero nano-injection of a heritable barcode library into the amniotic cavity at embryonic day 7.5 (E7.5). This approach (“NEPTUNE” - "neural plate targeting with in utero nano-injection", Mangold et al, 2021) allows us to specifically label the epiblast or ectoderm and the derivatives, including various skin compartments. We are currently focused on optimizing this technique to enhance labeling efficiency across distinct skin compartments. In parallel, we are optimizing the use of scRNA-seq library preparation methods of the barcoded embryos to increase experimental throughput in order to capture as many labelled cells as possible. Moving forward, our goal is to construct a high-resolution clonal map that reveals novel insights into skin development, with potential implications for regenerative medicine and the treatment of skin diseases.

Contact information:  jingyan.he@ki.se and karl.annusver@ki.se

Name: Kelli Somelar-Duracz

Project title: Psychedelic therapies for depression: A translational study.

Description: Major depression is a common mood disorder in the general population associated with disability and excessive mortality. Although currently available treatments for depression are effective in most cases, they exhibit limitations, such as delayed onset of treatment response, the need for chronic treatment, and ineffectiveness in about 30% of the patients. These limitations are particularly problematic for a population at elevated risk for suicide. Therefore, there is a major unmet need for the development of fast-acting antidepressants. During the past decade, there has been a renewed interest in psychedelics, such as the naturally occurring psilocybin, as potential treatments for a range of neuropsychiatric diseases. Initial findings from modern, randomized clinical trials suggest significant efficacy of psilocybin-assisted therapy in patients suffering from major depression. In contrast to medications currently used as first-line treatment, the antidepressive effects of psilocybin occur rapidly and are long-lasting (up to 6 months). However, more research is needed to determine the therapeutic potential of psychedelics for mental disorders. In addition, filling the gaps in understanding the mechanism of action underlying the anti-depressive effects of psilocybin is crucial for unlocking the full therapeutic potential of this class of compounds. My postdoctoral project aims to: (1) identify critical “hub regions” of the brain associated with the antidepressant effects of psilocybin, in mice and humans, (2) manipulate the cellular circuits and molecular mechanisms involved in these effects, using relevant mouse models of stress-related psychiatric disorders, and (3) investigate molecular biomarkers of psilocybin treatment response, using peripheral blood samples. To achieve these aims, a multidisciplinary approach, including advanced molecular, behavioral, and computational tools will be used. The expected outcome of the project is a better understanding of the cellular and molecular mechanisms mediating the rapid acting and sustained antidepressant effects of psilocybin.

Contact information: kelli.somelarduracz@ki.se

Name: Konstantinos Tsikonofilos

Project title: Neural and behavioral variability in humans and zebrafish: an integrative perspective.

Description: As the system with the formidable task of controlling all the body’s actions, the central nervous system is not static or fixed, but a highly dynamic and ever-changing complex system. In this project, two groups bring together their vastly different, but complementary views on the function of the central and peripheral nervous system. The Månsson group focuses on the central nervous system and particularly the brain, and how the moment-to-moment dynamics of its activity allow for flexible and adaptive behavior. In turn, these dynamics are disrupted in psychiatric disorders and can serve as biomarkers of disorders and treatment outcomes. The Ampatzis group focuses on plasticity, the ability of neural components to adapt at the molecular and structural levels to external conditions. This mechanism is at play in multiple contexts ranging from learning to recovery from injury. Together, the two groups explore how this variability in both structure and function changes in pathological conditions, and how it can serve as an integrative framework to bridge species and spatial scales. A major part of the project involves analyzing complex, high-dimensional data from recordings of brain activity in humans and from movement of behaving animals. Specifically, human functional magnetic resonance imaging (fMRI) datasets of patient cohorts with anxiety, or depressive disorders are analyzed using multivariate statistical methods that can distill the spatiotemporal dynamics of brain activity into meaningful neural signatures. A special focus of this line of work is in longitudinal designs with patients being scanned before and after treatment (both pharmacological and behavioral), allowing mechanistic investigations of the neural substrate of treatment efficacy. On the other hand, behavioral, video-captured data from a zebrafish model of spinal cord injury and regeneration are analyzed using state-of-the-art machine learning tools for motion tracking, and these tracking data are further analyzed to perform disease phenotyping.

Contact information: konstantinos.tsikonofilos@ki.se

Name: Linda Ok

Project title: Prenatal antidepressant treatment: from maternal serum signature to fetal brain response to ADHD risk and resilience.

Description: The first trimester of pregnancy is a critical period during which major placental remodeling and fetal brain neurogenesis occur. Maternal depression and antidepressant exposure during this critical period can profoundly influence the quality of the pregnancy and fetal neurodevelopment. However, the impact of depression and its treatment on the placenta and fetus during this crucial stage of neurodevelopment remains largely elusive. Our goal is to compare and contrast the effects of maternal depression and treatment during early gestation across the maternal-fetal interface from maternal serum to placental function, to neurodevelopment. Through this multidisciplinary approach which integrates proteomics, healthcare register and population cohort data, and multi-tissue organoid models, we aim to identify a molecular signature of these exposures, focusing on inflammatory markers. We believe that this comprehensive approach has the potential to reveal a risk and resilience signature in the mothers and allow us to assess the risks and benefits of perinatal antidepressant treatment in a new dimension. Ultimately, our findings could help predict child brain health outcomes and subsequently contribute to the clinical diagnostic or treatment toolkit for mental health and pregnancy, with benefits extending across generations

Contact information: linda.ok@ki.se

Name: Michelle Watts

Project title: Circular RNAs – a key component in human brain development and disorders?

Description: Circular RNAs (circRNAs) represent a unique class of RNA molecules that are enriched within the brain and formed following non-canonical back-splicing of exon-exon junctions. This project aims to identify circRNAs that may play a critical role in human brain development and to develop novel methods/new tools for characterising circRNA function. We aim to do this through dissecting genetic variants associated with autism spectrum disorder (ASD) followed by functional characterisation of circRNA variant effects. Using genomic data from >12,000 individuals in the SPARK autism cohort we have identified 928 unique, rare de novo variants in individuals with ASD that overlap with circRNAs from neurodevelopmental disorder-related genes. Additionally, we identified 7 rare variants within unique miRNA seed sites or RBP motifs spanning back-spliced junctions and are therefore found exclusively in circularised RNA isoforms. Using various metrics we have prioritised several variant-containing circRNAs for downstream analysis and validated their expression in our human neuroepithelial stem (NES) cell model. Currently we are working to characterise the functional roles of these candidate circRNAs and the consequences of ASD-associated rare variants. We believe this approach may uncover new circRNA functions in the healthy brain and reveal novel regulatory networks disrupted in neurodevelopmental disorders.

Contact information: michelle.watts@ki.se

Name: Nicolas Maino

Project title: Monitoring of newborn child immune system/microbiota relationship.

Description: Context Dysbiosis, or the dysregulation of a host’s bacterial diversity, has been shown to be implicated in a wide range of conditions ranging from irritable bowel syndrome to asthma. Yet, studying the microbiome is typically slow and relies on time consuming stool sample analysis in laboratory environment. To answer this need we present the concept of a transdermal biosensor operable at the point-of-care with minimal handling and time-toresult requirements. The device is simply operated and enables discrete sampling at a temporal resolution appropriate to capture microbiota dynamics. This device will enable new studies of the causal relationship between dysbiosis and pathological conditions. In particular, it aims to unravel the link between dysbiosis and irritable bowel flare onset as well as to the impairment of immune development in infants. Ultimately, this work may create a new framework for immunology studies where technological know-how bolsters the researchers reach into the microbiome

Contact information: nicolas.maino@ki.se

Name: Nikolaos Tsesmetzis

Description: Cutaneous lymphomas are rare, and they can be derived from different developmental stages of T-cells. Albeit most patients do not suffer from an aggressive form of the disease, those who will, have worse prognosis. Furthermore, in some types of CTCL, cancer cells can also be found in the blood, and the pathological mechanisms behind this are poorly understood. Hence, new treatment strategies are needed. SAMHD1 is an enzyme, that among other functions has a dNTP triphosphohydrolase activity, and plays an important role as a homeostatic regulator in intracellular dNTP pools. Moreover, this enzyme has been recognized as a tumor suppressor in different types of cancer. Interestingly, SAMHD1 expression has been shown to confer resistance against a plethora of nucleoside analogues used in chemotherapy both for AML as well as other haematological malignancies, making SAMHD1 expression a resistance factor for some chemotherapeutic treatments. Finally, in the pathological setting of CTCL, SAMHD1 protein expression has been shown to be expressed at high levels in leukemic CTCL compared to the low stage localized disease. In this project, by using two pairs of CTCL derived cell lines, (each pair being the parental cell line expressing SAMHD1 and one that SAMHD1 has been knocked out via gene-editing), we will produce drug response curves to bexarotene, a compound used for CTCL treatment and establish whether there is a SAMHD1-dependent response resistance and also if bexarotene treatment can affect SAMHD1 expression levels. Previous research has shown that SAMHD1 confers resistance to cytarabine treatment in Hut-78 cells. In this project we will test combination treatments of bexarotene and cytarabine and determine whether bexarotene-mediated SAMHD1 depletion can sensitize cells to cytarabine treatment. Through various functional experiments in this project, we will explore whether SAMHD1 expression relates to treatment resistance in CTCL and if we can develop new treatment strategies.

Contact information: nikolaos.tsesmetzis@ki.se

Name: Serena Piticchio

Project title: Connecting biological scales – atomic-level interpretation of genetic variants in rare diseases.

Description: Connecting biological scales – atomic-level interpretation of genetic variants in rare diseases. How can we determine whether a mutation – a change of a few atoms in a much larger molecule - can modify the native function of a protein potentially causing a disease? Clinicians often find variants of unknown significance (VUS) and it is clinically challenging to know whether they are disease causing. A tremendous amount of clinical and molecular laboratory work is needed to clarify their functional significance and establish their possible link with patient ́s diagnosis. Algorithms to evaluate variant significance heavily focus on sequence features, often ignoring the deepest interpretation level for amino acid changes: that of the 3D-structure of the proteins and its conformational dynamics, which dictates biological function. This project will explore the molecular causes of Genetic Skeletal Disorders (GSDs) at the structural-conformational level integrating information from multiple mutational and structural databases with bioinformatics and multiscale simulations. The higher diagnostic resolution for GSDs compared to other disorders due to specific radiographic features, often pinpointing a group of genes or specific pathways for closer exploration, offers an excellent model for the study of genotypephenotype correlations and for the validation of our approach that can be later used to explore other rare genetic diseases. Additionally, the exploration of pathogenic variants can provide new insights on the link between sequence-structure-conformation-function and how it is shaped by evolution as well as the mechanisms of GainOf-Function versus Loss-Of-Function variants.

Contact information:  serena.piticchio@ki.se

Name: Uta Hardt

Project title: Precise control of Tn5 fragment sizes for single-cell multiomics applications.

Description: Protocol improvements for single-cell multiomics applications In this KIRI project, we are evaluating protocol alterations for single-cell multiomics sequencing applications. These methods are used to study the genome, the expressed transcriptome and the regulatory epigenome of tissues or whole organisms at the single-cell level. In particular, we are interested in the library preparation process for next-generation sequencing. The fragmentation and insertion of amplification-handle sequences in this process is mediated by the bacterial Tn5 transposon system that has been adapted for use in molecular biology systems. This step mediated by Tn5 is also called tagmentation and is necessary in many multiomic methods. In our studies, we study the effects of Tn5 modulation by different means and aim to design a protocol that allows precise control of the tagmentation process at manageable cost in yield. Controlling this step in library preparation more precisely increases quality and quantity of information gained from multiomic sequencing applications helping to advance biomedical knowledge.

Contact information:  uta.hardt@ki.se

Name: Yanan Chen

Project title: Revealing the enteric-sympathetic networks regulating pancreatic secretion.

Description: The pancreas is critical for nutritional intake and the general metabolic state of the body through its exo- (secretion of digestive enzymes) and endocrine functions (release of insulin, glucagon). Besides the parasympathetic / sensory vagus nerve, the pancreas also integrates information from sympathetic celiac ganglia and the enteric nervous system. However, how the latter two extrinsic nervous systems play a role in the regulation of pancreatic homeostasis remains poorly explored. Although the direct enteric-pancreatic innervation from the duodenum has been described 30 years ago, the physiological relevance of this connection is still not established. This project will comprehensively characterize the neuronal components of direct duodenalpancreas and indirect enteric-celiac-pancreas circuits and elucidate the function of enteric/sympathetic neurons in regulation of pancreatic exo- and endocrine secretion.

Contact information: yanan.chen@ki.se

Name: Zhilei Xu

Project title: Mapping Individual Molecular Connectomes in Alzheimer’s Disease.

Description: Individual molecular connectome mapping provides greater sensitivity in monitoring Alzheimer’s Disease progression A new method—individual molecular connectome mapping—developed by Xu et al. provides greater sensitivity in monitoring Alzheimer’s Disease (AD) progression than conventionally used methods. The researchers predict that the new method will offer a promising avenue for personalized medicine strategies and testing the effectiveness of current clinical trials in AD. Mapping individual differences is crucial to improve personalized medicine approaches in AD, which is characterized by strong inter-individual variability in the accumulation patterns of tau and amyloid-β pathology. Xu et al. introduced a comprehensive framework to explore the individual progression of Aβ and tau pathology across the AD continuum by mapping individual molecular connectomes using longitudinal amyloid and tau positron emission tomography (PET) dataset. They demonstrated that these connectomes constitute a unique fingerprint, capable of identifying a single individual from a large group of subjects, serving as enhanced markers to discriminate different diagnostic groups across the AD continuum. Alterations in these connectomes discriminated different diagnostic groups and predicted cognitive decline to a higher extent than conventional PET measures. The researchers introduced a novel genespecific transcription network analysis that linked individual tau and amyloid connectomes to a common transcriptomic profile of apoptosis, with the tau connectome being specifically related to pyrimidine metabolism, and the amyloid connectome to histone acetylation. These findings indicates that the susceptibilities of individual molecular connectomes correlate closely with transcriptomic profiles that are directly relevant to AD. Collectively, these results demonstrated individual molecular connectomes of significant clinical relevance to monitoring disease progression and to evaluating the effectiveness of treatments across the AD continuum.

Contact information: zhilei.xu@ki.se

Name: Hemalatha Babu

Project title: CD8 T cell diversification during dengue virus infection.

Description: During acute viral infection, naïve CD8 T cells differentiate into a heterogeneous population of antigen-experienced CD8 T cells. Some of these CD8 T cells kill the virus infected host cells during a phase that is called the effector phase of the immune response. Following that, T cell memory is established with core features such as long-term persistence and ability to mount secondary immune response upon reinfection. This stage is called the memory phase of the immune response. In this study, we aim to identify the core features that distinguish effector and memory phase T cells in humans during acute and convolesent phases of dengue infection.

Contact information: hemalatha.babu.2@ki.se