Sugars maketh the brain: investigating the role of neuronal glycocalyx in shaping the architecture of emerging circuits
ERC Consolidator Grant (ERC-2024-COG-GLYCOCIRC), 2025-2030
Neuronal glycocalyx has been recently recognised as an active agent that contributes to neuronal synapse formation, neuron excitability, as well as neuron-autonomous and microglia-dependent brain network remodelling. In particular, the glycan-terminating sialic acids, which often dominate the ends of the chains of glycoproteins and glycolipids on the neuronal surface, are required for appropriate brain development and function. Interestingly, almost a fifth of sialic acid biology genes have human-specific changes and aberrant neuronal sialylation and desialylation are implicated in different neurodevelopmental and neuropsychiatric conditions. Thus, we investigate the critical role of neuronal glycocalyx and its component sialic acid, in particular, in the formation of the unique human brain. We merge our expertise in biochemistry and neuroscience to tackle this challenging area of research to further our knowledge of brain sialome through an evolutionary approach.
Designed adenovirus vectors for cell-specific delivery of genome editing tools
Horizon Europe Hop-On Facility (HORIZON-WIDERA-2023-ACCESS-06-01-iAds Hop-On), 2025-2027
The discovery of CRISPR/Cas systems provides new opportunities to treat human disorders at the genome level, including neuropathologies, which have an immense and still increasing burden on our society. However, the advancement of gene editing therapies for human disease has been lagging behind the development of relevant molecular tools, in part, due to the lack of suitable delivery vectors for CRISPR/Cas systems in vivo. The development of intelligently designed adenovirus vectors opens new avenues for the delivery of state-of-the-art genome editing tools into the tissue of interest to revert disease-causing gene mutations. Therefore, we contribute to the iAds consortium by developing clinically relevant tests of iAds vectors using human tissue and incorporating genome editing tools in vectors targeting the heart and brain.
Early metabolic programming affects hypothalamus yielding eating disorders
ERA-NET NEURON Joint Transnational Call 2024 “Bidirectional Brain-Body Interactions”, 2025-2028
Eating disorders are neuropsychiatric conditions characterised by severe and persistent disturbance in eating behaviours and associated distressing thoughts and emotions. Despite their individual and socio-economic burden, the aetiology of eating disorders is still poorly understood, and suitable interventions are lacking. The risks for eating disorders are increased by the alterations of brain development in the prenatal and perinatal period due to adverse maternal factors, such as unhealthy maternal diet and obesity. In particular, a maternal high-fat diet affects the hypothalamus, the brain region involved in feeding control. Therefore, we aim to define how maternal metabolic programming during the perinatal period disturbs the microglia-neuron interactions in the hypothalamus, increasing the risk of eating disorders in the offspring. We employ both exploratory and hypothesis-driven approaches using a variety of models, ranging from hiPSC-derived hypothalamic-like neurons and microglia as well as brain organotypic cultures, to Drosophila and mouse models. We translationally validate the results obtained in animal models by examining the lipids and non-coding RNAs in human milk samples. Altogether, this interdisciplinary consortium aims to define molecular and cellular mechanisms of the development of eating disorders, contributing to our understanding of their aetiology and proposing possible targets as well as timing for risk-mitigating interventions.
Early intervention with mTOR inhibitors for neuropsychiatric symptoms in Tuberous Sclerosis Complex: unveiling developmental windows
DAINA3 Polish-Lithuanian Funding Initiative by the National Science Centre (NCN) and the Research Council of Lithuania (RCL), 2025-2028
Tuberous sclerosis complex (TSC) is a multisystem genetic disorder characterised by benign tumour growth, primarily affecting the central nervous system, kidneys, and skin. Neuropsychiatric symptoms, including epilepsy, developmental delay, cognitive impairment, and behavioural issues, pose significant challenges to patients' quality of life. Current therapeutic approaches, though beneficial, are predominantly symptomatic and lack efficacy in modifying long-term outcomes. Recent advancements propose allosteric inhibitors of mTORC1, particularly everolimus, as potential therapeutic avenues for TSC. However, their effectiveness in addressing neuropsychiatric manifestations remains limited, possibly due to delayed administration beyond critical developmental periods. Understanding the optimal timing for intervention is crucial for maximizing therapeutic benefits. In this comprehensive study, we aim to identify the developmental period during which early intervention with mTOR inhibitors effectively mitigates neuropsychiatric symptoms in TSC. Using murine models, we track developmental changes in synaptic function-related gene expression, pinpointing the onset of molecular alterations. Subsequently, we will investigate whether early administration of everolimus during this critical window reverses aberrant gene expression patterns. Our research holds promise for informing clinical practice, emphasising the importance of early diagnosis and intervention in TSC.
Neurobiological mechanisms of the environment – plasticity – behaviour interaction
ERA-NET NEURON Joint Transnational Call 2023 “Resilience and Vulnerability in Mental Health”
Mental health disorders are among the most important health problems worldwide. Since the onset and progression of both disorders are highly affected by contextual factors, we propose that plasticity is an underlying mechanism in both resilience and vulnerability, depending on the environmental context. We hypothesise that it is the environmental valence that determines whether the brain networks are driven towards resilience or vulnerability, and the plasticity states determine to what extent these environmental effects become permanent. EnviroMood uses a back-translational approach to elucidate the environment-plasticity-behaviour interaction and its underlying mechanisms: starting from a proof-of-concept trial in humans to test a differential modulation of mood by behavioural interventions with positive and negative valence in different states of plasticity. We then back-translate this approach to animal models in rodents and assess vulnerability and resilience in mouse behaviour under different environmental conditions and plasticity-related drug treatment. Furthermore, we assess drug effects on AMPAR expression, spine and network plasticity and use behavioural and ex vivo experiments to focus on the role of the TrkB pathway, amygdala, and microglia. A more profound understanding of the environment-plasticity-behaviour interaction is critical to the development of innovative interventions to promote mental health.
https://www.neuron-eranet.eu/projects/EnviroMood/
Gene editing to reverse aceruloplasminemia phenotype in mouse and hiPSC models
Lithuania-Taiwan bilateral call by the Research Council of Lithuania and the National Science and Technology Council of Taiwan, 2024-2026
Aceruloplasminemia (ACP) is a rare, adult-onset, autosomal recessive disease characterised by the absence of ceruloplasmin (CP), a protein that binds copper in the blood, which is essential for systemic iron transport and homeostasis. CP possess ferroxidase activity vital for iron export from various cells. CP deficiency results in excess iron accumulation in various organs, particularly the pancreas, liver, and brain. There is no effective cure for ACP at the moment. Current treatment for ACP depends on iron chelation therapy; however, short half-life time in the blood, the capacity to cross the blood-brain-barrier, and potential side effects of the iron chelators complicate their therapeutic results. Enzyme replacement therapy (ERT) was also proposed but was restricted to the patient’s humoral response; thus, there was limited clinical evidence for its long-term efficacy. In this project, we develop a humanised ACP mouse model and use a previously established ACP patient-derived induced pluripotent stem cells as platforms to develop gene therapy using the latest genome editing tools, herpes simplex virus vectors, and lipid nanoparticle technology. We aim to find a cure, or at least an alternative treatment, for this incurable disease, establishing a workflow that will serve as a paradigm for the preclinical development of CRISPR therapies for other genetic diseases as well.
Pan-European Network for Neuroscience Research Infrastructure and Strengthening of Support Capacities
Horizon Europe Pathways to Synergies (HORIZON-WIDERA-2023-ACCESS-04-PANERIS), 2024-2026
PANERIS aims to elevate the research and innovation (R&I) capacities in neuroscience within Widening Countries by focusing on the impact of obesity and addiction on brain health across the lifespan. This project seeks to address critical challenges in public health through a multidisciplinary approach, enhancing the understanding of these conditions and developing effective intervention strategies. PANERIS will serve as a coordination and support platform, strengthening the internationalisation and competitiveness of neuroscience research in Lithuania, Poland, and Portugal. By partnering with a leading research institute in Spain, PANERIS will advance the participating countries’ R&I infrastructure, fostering collaboration and capacity building to achieve excellence in neuroscience research and innovation.
The application of gene editing tools for monogenic lysosomal storage disorders
Research Council of Lithuania funding for competitive PhD position, 2023-2027
Lysosomal storage diseases comprise a group of approximately 70 inherited diseases caused by defects in lysosomal genes. The pathophysiology of these conditions is complex, affecting multiple organ systems and, in most cases, the nervous system. Currently, treatment strategies for these diseases aim to reduce the severity of symptoms and delay disease progression, but they are not curable with available therapies. Most lysosomal storage diseases are monogenic, and the mutations that cause them are usually point missense or nonsense mutations or small deletions or insertions. Thus, they are a suitable target for the development of personalised therapies based on CRISPR/Cas gene editing technology. During this doctoral project, we apply gene editing tools in cell, tissue and/or animal model systems to demonstrate their potential to cure these diseases and to become the basis for translational research in the future.
Targeted CRISPR-Cas Delivery into Mammalian Nervous System
"University Excellence Initiatives" programme of the Ministry of Education, Science and Sports of the Republic of Lithuania (Measure No. 12-001-01-01-01 "Improving the Research and Study Environment"), 2024-2026
European Regional Development Fund grant agreement No 01.2.2-CPVA-V-716-01-0001 with the Central Project Management Agency (CPVA), 2021-2023
Currently, the diseases of the nervous system are in the spotlight like never before. We see a threatening rise of both neurodegenerative diseases in the ageing population, as well as neurodevelopmental disorders in children. Compared to the rest of the body, the treatment of the brain has its own challenges. Neurons, the major cell type that conveys brain function, are post-mitotic and have limited regenerative capacity, thus limiting the treatment approaches that can be applied. Furthermore, the brain is screened from the circulating blood by the selective blood-brain barrier, which frequently prevents the accessibility of drugs to the brain and limits their applicability in brain disorders. Fortunately, developing technologies create a platform not only to better understand our brain in health and disease, but to attempt to remediate observed deficits, alleviate the symptoms and halt or even reverse the pathology. The discovery of the CRISPR-Cas system and its application to specifically edit genes in vivo provide new opportunities to treat neuropathologies at the genome level. Therefore, we apply our effort to develop CRISPR-Cas applications for the mammalian brain. We will explore different delivery techniques, screen for the most suitable Cas enzymes and apply them in mouse models and in human brain tissue with the potential to translate to clinical developments.
