Ongoing projects

Glucose variability, affective well-being and cognition in people with type 1 and type 2 diabetes: investigation of vulnerability and resilience factors in naturalistic contexts with ambulatory monitoring

Abstract
Background: Type 1 diabetes (T1D) and type 2 diabetes (T2D) are chronic diseases characterised by glucose fluctuations. Laboratory studies suggest that cognitive abilities are impaired in hypoglycaemia and hyperglycaemia. Due to technological limitations, the relationship between naturally occurring glucose fluctuations and cognitive fluctuations has so far been insufficiently investigated. Aim of the project: The aim of the project is to investigate temporal relationships between the variability of blood glucose levels, emotional well-being and cognitive performance. Other potential influencing factors (e.g. physical and social environment, physical activity, sleep quality) will be taken into account. Methods: A total of 4 samples will be included. Participants with T1D (n = 50), T2D (n = 50), and with prediabetes (n = 50) as well as a healthy control group (n = 50) will be analysed for 14 days using continuous glucose monitoring (CGM), actigraphy, electrocardiography and Ecological Momentary Assessment (EMA; cognitive mass and self report) at 5 daily time points. CGM will be performed with the support of CGM sensors (study devices). Expected results: We anticipate that cognitive performance and well-being variables will decline with both low and high blood glucose levels, and that we will find individual differences in cognitive vulnerability to glucose fluctuations. Based on the results, new funding applications will then be submitted to deepen the research.

Expression, characterisation and studies on the directed genetic repair of pathogenic desmin variants (DES) using recombinant adeno-associated viruses (AAVs) in human and porcine cardiac myocardial slices

Abstract

Stable treatment of desminopathies (OMIM, *125660) by gene replacement therapy of the DES gene is limited by dominant-negative inheritance and heart transplantation is currently the only curative treatment option in end-stage disease. Basic molecular biological laboratory studies on the effect of pathogenic DES mutations on living myocardial slices (LMS) are currently limited by the low efficiency of conventional transfection reagents. In the "AAV4Desmin" project, the cooperation partners are therefore applying for funding for the initial development of a DES gene (correction) therapy with the latest genome editors, which are to be specifically introduced into human LMS using clinically tested gene shuttles, the recombinant adeno-associated virus particles (rAAV). For this purpose, an optimal rAAV for LMS transduction is first determined from a panel of possible candidates. In the second step, pathogenic DES variants are inserted into human and porcine LMS using the selected rAAV to map the mostly heterozygous situation of the affected individuals in order to investigate the structural and functional influences of these genetic variants. In the final third work package, a pathogenic DES variant is genetically corrected in the LMS model using rAAV-mediated genome editing. The experiments carried out will prepare the application for DFG funding for preclinical mouse studies. The cooperating project partners are ideally positioned for successful joint project implementation thanks to their many years of experience in the field of rAAV vector design and production as well as basic research on desminopathies, and the start-up financing formalises and expands an existing cooperation between Bielefeld University and the HDZ-NRW.

AFM-based contraction studies on RBM20-deficient cardiomyocytes

Abstracts:

Dilated cardiomyopathy (DCM) is a common cause of heart failure with a prevalence of 1:2500-1:250. In over 40% of cases, DCM can be attributed to genetic causes. Mutations in the gene RBM20, which codes for the RNA-binding motif protein 20 (RBM20), are also associated with DCM. RBM20 acts as a splicing factor and influences the splicing and thus also the function of numerous cardiac genes. These include sarcomeric proteins such as titin as well as proteins involved in calcium handling in cardiomyocytes. Although the main target genes of RBM20 are largely known, the effects of mis-splicing on cardiomyocyte contraction and excitation-contraction coupling have only been incompletely investigated. The aim of the proposed project is to investigate cardiomyocytes derived from induced pluripotent stem cells with corresponding RBM20 mutations with regard to contractility and calcium handling using confocal microscopy and atomic force microscopy combined with fluorescence microscopy. Based on the broad database generated, RBM20-associated pathomechanisms will be identified in comparison with isogenic controls. This approach could establish a bridge between molecular interactions and the associated clinical phenotype and enable a deeper understanding of pathogenic processes, which could also contribute to the identification of therapeutic targets.

Energy and radical flow in diabetic cardiomyopathy

Abstract:

Diabetes mellitus and in particular its secondary complications are on the rise worldwide. Despite good therapeutic success in terms of metabolic control, concomitant diseases continue to occur. This justifies further research in the field of metabolism. The aim of this project ending date is the molecular understanding of diabetic-induced heart failure at the level of energy production and supply. Mitochondria and peroxisomes are therefore at the centre of interest as the responsible cell organelles. In cardiomyocytes derived from human inducible pluripotent stem cells, metabolic efficiency, ATP production, oxidative stress, ER stress and Ca2+ homeostasis are therefore analysed under diabetic and non-diabetic conditions. In peroxisome 5-deficient cells, metabolic performance will also be analysed with a focus on the development of diabetes mellitus. Therapeutic options will be tested by using specific interactors (inhibitors and activators) of individual metabolic pathways. As part of this project, mitochondrial and peroxisomal involvement in the development of metabolically induced cardiomyopathy and the interrelationship between the cell organelles are being investigated for the first time. The cooperation partners are each contributing their core expertise in order to prepare further follow-up projects in a targeted manner.

Influence of acute coronary syndrome and diabetes mellitus on the apolipoprotein profile between the sexes - a 6-month follow-up study

Abstracts:

Acute coronary syndrome (ACS) is a life-threatening coronary artery disease caused by a sudden disruption of coronary blood flow that can lead to myocardial infarction and death. Secondary prevention after diagnosis and stabilisation of the patient are crucial to prevent adverse coronary events. Interestingly, the course of the disease varies according to gender, and younger women in particular have a worse short- and long-term course. In addition, women diagnosed with diabetes mellitus are more prone to cardiovascular disease and myocardial infarction than men. However, the mechanism behind these sex-related differences in ACS or ACS-diabetic patients is not yet fully understood and represents an unmet clinical need. Apolipoproteins (Apo) are structural and functional components of lipoprotein particles involved in lipid metabolism. They possess not only physiological but also pathological properties that are associated with the development of cardiovascular diseases. Among all apos, apolipoprotein B (apoB) is the best studied and is considered a superior biomarker for cardiovascular risk compared to the traditional risk factor low-density lipoprotein (LDL) cholesterol. However, the comprehensive study of Apos in this context is limited, as there are no commercial tests that can be used to perform simultaneous Apos measurements. Given the lack of knowledge about the association of Apos with sex-specific progression of ACS disease and how diabetes influences these changes, the first aim of this study is to develop a mass spectrometry-based assay for the simultaneous quantification of 13 Apos. The second aim is to determine their levels in ACS and diabetic ACS patients after a 6-month follow-up between the sexes.

Explainable deep learning classification of paediatric myocarditis

Abstract:

Diagnosing myocarditis (inflammation of the heart muscle) is difficult. The gold standard for detection with a single procedure is the invasive biopsy (removal of heart muscle tissue), which, however, has a low sensitivity. Another promising procedure is magnetic resonance imaging (MRI). This procedure is non-invasive and can visualise the myocardial oedema (water retention), hyperaemia (excessive blood flow), scarring and fibrotic changes caused by the inflammation. To date, the Lake-Louis criteria (Friedrich et al., 2009; Ferreira et al. 2018) have been used to diagnose myocarditis with MRI. This project aims to investigate whether a deep learning (DL) method is able to diagnose myocarditis in children based on MRI images. For this purpose, already collected and local data of about 60 children of the MYKKE registry1 from the HDZ-NRW will be used. Clinical data and functional parameters of the heart (e.g. ejection fraction, strain, etc.) already collected will also be included in the decision, which have rarely been considered in the diagnosis to date. One focus of the project is on the application and investigation of methods of explainability of AI (XAI) to represent features and functional parameters that the DL procedure uses for diagnosis. This can support doctors in diagnosis and provide insights into diagnostic criteria.

Therapeutic effect of nitrated fatty acids on German and English mouse heart muscle cells in a model of heart failure

Abstracts:

Nitrated fatty acids (NO2-FA) are electrophilic, anti-inflammatory mediators that are formed endogenously during ischaemic damage to the heart muscle, but can also be administered after chemical synthesis as a therapeutic molecule in experimental animals or patients in the context of clinical studies. Results from previous studies show NO2-FA to be a promising new therapeutic molecule for heart disease. Treatment of mice with nitrated fatty acids (e.g. nitro-oleic acid, NO2-OA) significantly reduced left heart failure in a model of HFpEF. However, the exact mode of action is unclear as NO2-FA can affect multiple processes, including intracellular Ca2+ handling and mitochondrial function. Therefore, we aim to characterise the effects of NO2-FA treatment at the molecular level using isolated cardiac myocytes from two different mouse models, both in the HFpEF model and in a mouse model with an endogenous mitochondrial redox biosensor. Subsequently, we will use a crossover mouse model (HFpEF x redox biosensor) to simultaneously investigate the effects of NO2-FA on Ca2+ balance and mitochondrial respiration. We expect that this start-up project will intensify the collaboration between the Faculty of Medicine OWL and the HDZ NRW and that the results of this start-up project will elucidate the cardiac mechanism of action of NO2-FA in a gender-dependent manner and contribute to expanding the therapy of various types of heart disease to include the NO2-FA substance class.

Cell organelle-based mechanisms and therapy of right heart failure

Abstract:

Heart failure, i.e. the inability of the heart to perform adequately to meet oxygen and nutrient requirements, is one of the most common causes of death in industrialised countries. This syndrome can be caused by various diseases, which can affect both chambers of the heart or just one of the two ventricles in isolation. Cardiac muscle cells are among the cells with the highest energy consumption in the body, which is why substrate metabolism plays a decisive role in their performance. The metabolic cell organelles, the mitochondria and peroxisomes, have therefore become the focus of current research. While potent pharmacological therapeutics are known for the weakness of the left ventricle (guidelines), these do not exist for the therapy of the right ventricle, which differs significantly in structure and pathomechanisms. Although it has been recognised that disturbances in the function of metabolic cell organelles occur in the context of right ventricular failure, the causes, mechanisms and interaction of both organelles are poorly understood. As these are also structures for important pharmacological targets, the project proposed here aims to investigate the co-regulation of peroxisomes and mitochondria, the interplay of substrate metabolism and mitochondrial/peroxisome integrity and possible therapeutic options in the development of right heart failure using a mouse model for right heart failure. Wild-type mice and two genetically modified mouse lines will be used for this purpose. In this way, the project will make an important and innovative contribution to the development of therapy options for patients with chronic right heart failure.

The proteome of the human heart peroxisomes

Abstracts:

Peroxisomes are multifunctional organelles involved in diverse processes including lipid metabolism, redox balance, calcium regulation and other mechanisms that are critical for the maintenance of cellular homeostasis. Interest in peroxisomes was sparked by the discovery of a group of hereditary diseases such as Zellweger syndrome and Refsum disease, which are caused by defects in peroxisome biogenesis or dysfunction of specific peroxisomal proteins. While their roles in organs such as the liver and kidneys are well understood, the contributions of peroxisomes to cardiac function, particularly in the context of heart failure (HF), remain largely unexplored. Our research aims to elucidate the role of peroxisomes in the pathogenesis of HF. This will be achieved by a comprehensive analysis of peroxisome fractions from explanted, diseased and - if available - rejected donor hearts using quantitative proteomics techniques. The results will deepen our understanding of the role of peroxisomes in cardiac physiology and disease, identify novel proteins and integrate them into the functional networks of cardiomyocytes. This project has the potential to identify novel therapeutic biomarkers and signalling pathways that could pave the way for innovative treatments and significantly improve outcomes for HF patients.

Virtual reality for the medical care of people with intellectual disabilities

Abstract:

People with congenital or acquired cognitive disabilities, such as intellectual disability or acquired brain injury, often experience increased anxiety or uncertainty during medical examinations. The "VR-IM" project aims to reduce these fears through the use of virtual reality (VR). Through VR-based training, patients are familiarised with the medical intervention process, the treatment room and the equipment and taught coping strategies to reduce their anxiety and facilitate medical care. A key aim is to empower patients by enabling them to actively carry out treatment steps themselves in the VR environment. This promotes their self-determination and self-efficacy. We expect that the VR warm-up will not only reduce treatment costs by saving valuable device time, but also break down barriers in the healthcare system. The research is relevant for both the clinical and outpatient sectors and can initiate a rethink in the treatment of people with disabilities.

The readthrough isoform of aquaporin-4 (AQP4) - a specific target structure of neuromyelitis optica (NMO) autoantibodies?

Abstracts:

Aquaporin 4 (AQP4), a water-selective membrane channel mainly expressed in astrocyte protrusions at the blood-brain barrier, is the target structure for autoantibodies in neuromyelitis optica spectrum diseases (NMOSD). These autoantibodies cause inflammatory diseases of the central nervous system (CNS) and produce a clinical picture that is difficult to distinguish from other chronic inflammatory diseases of the CNS, such as multiple sclerosis (MS). AQPs are expressed in different isoforms, one of which is generated by the functional translational readthrough (FTR) co-discovered by the applicant. The isoforms are involved in the formation of clusters, which are a prerequisite for functional water transport and the binding of autoantibodies. In the proposed project, we will investigate for the first time the disease relevance of the FTR, also with regard to sex-specific expression and pathogenicity, using the example of the elongated AQP4 isoforms (AQP4x). We will analyse the function of AQP4x in the aggregation of isoforms and the binding of autoantibodies in order to create the basis for more sensitive and targeted diagnostics and therapy.

Mobilisation of children after trauma or surgery and children with depression with the Mobirobot

Abstract:

Physiotherapy is important for children after trauma or surgery to prevent pneumonia, cardiovascular impairment and/or restricted joints and for children with depressive disorders. However, experienced paediatric physiotherapists are rare and expensive. In this study, we want to use humanoid robots that perform typical movement and motivational tasks to support physiotherapists in the mobilisation of children on paediatric wards and in outpatient settings. Robots are particularly suitable for this task, as children have a positive attitude towards robots and the embodiment of robots is advantageous for demonstrating movement exercises and influencing motivation and compliance. However, their transfer depends on their integration into clinical and outpatient settings and routines as well as their acceptance, compliance and engagement of children, parents and healthcare professionals. In the medium term, we want to evaluate the efficiency of the robots using validated instruments and scoring systems. The expected results of the proposed project will provide a basis for further funding by national institutions to investigate the efficiency of robots in the mobilisation and rehabilitation of normal children as well as children with disabilities.

Sex-specific differences in TRESK-TRPV1 signalling in iPSC-derived sensory neurons of migraine patients

Abstracts:

Migraine is a common neurovascular disorder with complex molecular mechanisms and a variety of genetic backgrounds, including a loss-of-function mutation in the TWIK-related spinal cord potassium channel (TRESK). While the prevalence in childhood is similar in both sexes, women are affected three times more frequently than men with increasing age. There are indications that this difference is mediated by hormones. These have been shown to influence the excitability of trigeminal nociceptors by modulating the receptor transient receptor potential vanilloid 1 (TRPV1). In addition, it has been shown that TRPV1 can be activated by the inhibition of TRESK, leading to an increased release of calcitonin gene-related peptide (CGRP), which plays a central role in migraine pathophysiology. Since animal models are ethically questionable and experimental results are not readily transferable to humans, human induced pluripotent stem cells (iPSC) represent a modern technique for investigating the pathophysiology of various diseases. In the proposed project, in collaboration with Priv.-Doz. Dr Witte (Anaesthesiology, Intensive Care, Emergency Medicine, Transfusion Medicine and Pain Therapy, EvKB, Bielefeld, Germany), we want to establish a cohort of migraine patient-derived iPSCs and corresponding controls. The iPSCs will be used to generate patient-specific nociceptive neurons that will enable the analysis of sex-specific differences in migraine pathology with a focus on TRESKTRPV1 signalling.

Combined molecular targeting of acoustic neuroma and meningioma

Abstracts:

Vestibular schwannomas (VS) and meningiomas (MG) are tumours of the head and neck, brain or spine. They share a common subtype defined by the deficiency of the tumour suppressor gene NF2 and are otherwise similar in pathogenesis. Despite their predominantly benign nature, they often cause severe defects in the brain and head and neck region due to their localisation. This can impair vital functions such as eating, speaking or hearing or lead to mental damage. Surgical treatment of VS can also lead to paralysis of the facial nerve and deafness, while surgery for MG can result in injury to the brain and spine, which can then cause neurological deficits, seizures and paralysis of the extremities. As a result, both tumours often lead to a reduced quality of life and participation in social life. In our study, we therefore want to investigate molecularly targeted drugs that specifically inhibit signal transduction in VS and MG cells. This should create new possibilities to shrink the tumours before surgical removal in order to reduce the damage caused by this treatment. To date, there is no drug therapy available for these tumours. To set ourselves apart from other studies in this field, we want to focus on finding synergistic combinations of inhibitors that can attack the tumour cells much more effectively than single agents. We will also examine tumour cells from female and male patients separately in order to detect gender-specific differences in the efficacy of the inhibitors. Meningiomas are twice as common in women compared to men. Overall, we are confident that the alliance between the Department of Otorhinolaryngology and the Department of Neurosurgery can develop an approach for the drug therapy of VS and MG cells in order to prepare subsequent clinical trials that will improve the quality of life and social participation of patients in the long term.

Molecular mechanisms for variability in the efficacy of non-steroidal anti-inflammatory drugs in chronic rheumatic pain: a pilot clinical study on the role of cyclooxygenase-2 pathway activation in the analgesic efficacy of etoricoxib.

Abstract:

Chronic pain limits social participation through persistent functional, emotional and cognitive impairment. Non-steroidal anti-inflammatory drugs (NSAIDs) are an important component in the management of inflammatory and, in some cases, non-inflammatory pain. They work by inhibiting the cyclooxygenase (COX)-2-dependent formation of prostaglandins. However, a significant proportion of patients do not respond to NSAIDs with sufficient pain relief and require therapies with significantly less favourable side effect profiles, such as opiates. The underlying molecular mechanisms of non-response to NSAIDs are unclear. In this 'deep-phenotyping' pilot study, we investigate immune-molecular causes of inadequate pain relief in 3 rheumatic diseases characterised by inter-individual variability in response rates to NSAIDs: Axial spondyloarthritis and rheumatoid arthritis as causes of inflammatory pain but with variable response to NSAIDs, and fibromyalgia as a disease with low NSAID response rates. We are investigating the hypothesis that the degree of analgesic efficacy of the NSAID etoricoxib-despite biochemically proven inhibition of COX-2-is associated with a pre-existing, possibly differential activation of the COX-2 signalling pathway in immune cells. This multidisciplinary co-operation project pursues 4 overarching objectives: (1) The research topics of brain-impairment-participation and gender-sensitive medicine will be further developed. (2) Innovative methods for immunophenotyping using single cell RNA sequencing will be established at the new OMICs Facility and new AI-supported biomarkers will be sought. (3) The foundations are being laid for externally funded follow-up studies to identify predictive biomarkers with the aim of increasing individualisation of therapy with NSAIDs. (4) Efforts are being made to improve the care of people suffering from chronic pain.

Specifics of inclusive medicine in surgical clinical pictures

Abstract:

Background: People with a cognitive impairment (e.g. intellectual development disorder (IDD), autism spectrum disorder) suffer more frequently from physical (99%) and mental (approx. 40%) illnesses than the general population. Overall, their life expectancy is reduced by around 20 years. Chronic and secondary health conditions in particular lead to premature death. There is little data available on diseases that require surgical treatment. The results on postoperative mortality rates in hospital, the occurrence of postoperative complications and the length of stay are contradictory. In emergency admissions of people with cognitive impairment to visceral surgery, people with SIE showed a more complex clinical picture, altered symptoms on initial presentation due to ileus and a longer time from onset of symptoms to surgery. Depending on the clinical picture, people with SIE require an individualised treatment concept that takes into account personal characteristics and possible longer post-operative treatment times]. In 2006, the UN Convention on the Rights of Persons with Disabilities (UN CRPD) was adopted by the General Assembly of the United Nations (UN) [8]. Article 25 of the UNCRPD stipulates that healthcare services for people with disabilities must be easily accessible and of equal quality to those for people without disabilities. In addition, special needs arising from the disability itself must be covered. In order to improve healthcare for people with a cognitive impairment, it is essential to be aware of frequent care occasions and specific needs in inpatient care. Research gap: Current research lacks clinical data on the inpatient surgical care of people with SIE, in particular on the common and individual clinical pictures, special features of the surgical procedure, length of stay, complication rates and the treatment of pain. Object of research: This research project analyses data on pre-, peri- and post-operative care in surgical clinics. The research questions focus on frequent reasons for admission, the stage of disease on admission, the timing of decision-making processes, treatment pathways, types of surgical care and peri- and postoperative complications in adults with SIE. Methods: Retrospective cohort study in the Clinics for Trauma Surgery and Orthopaedics, Neuro-, Thoracic-, Visceral and Vascular Surgery of the EvKB and the Clinics for Trauma Surgery and Orthopaedics, Thoracic Surgery and General and Visceral Surgery of the Lippe Hospital. Cases of adults with an intellectual development disorder who were treated in the clinics between 1 January 2013 and 31 December 2023 will be examined. Significance: The aim of this study is to identify characteristics and peculiarities in the inpatient surgical treatment of people with an intellectual development disorder.

The role of steroid hormones in COVID-19 and post-viral syndrome

Abstract:

Women contract SARS-CoV-2 infections more frequently than men. However, morbidity and mortality are much lower in women than in men. Initial studies indicate an influence of sex hormones on the course of a SARS-CoV-2 infection. The development of a post/long COVID syndrome appears to be linked to changes in cortisol metabolism in the initial phase of the disease. The University Medical Center OWL and its three sites are part of the National Pandemic Cohort Network (NAPKON, www.napkon.de). During the coronavirus pandemic, 133 patients were recruited in the cross-sector cohort (SUEP), more than at any other site. Detailed data is available from these patients on their personal details, the course of their illness and medication, as well as their post-inpatient course. Biosamples were collected at various points in time, preserved at the clinics and are now available for research. The collaborative project aims to uncover endocrine mechanisms involved in the course of a SARS-CoV-2 infection. It is planned to analyse 15 sex and adrenal hormones and their precursor hormones using highly specific liquid chromatography tandem/mass spectrometry in order to examine their influence on the course of the disease and the development of a post/long COVID syndrome. At the same time, targeted genome analysis is used to search for changes in oestrogen receptors 1 and 2 as well as the androgen receptor. After analysing the hormones, a decision is made as to whether further genome analyses are necessary (e.g. cortisol receptor). The analysis of the data is supplemented by machine learning and artificial intelligence methods.

The role of the microbiome in colorectal cancer development - methods for analysing and deciphering the microbiome-host interaction

Abstract:

Colorectal carcinoma is the third most common cancer in Germany. It is the second most common cause of cancer-related death worldwide, with a recent dramatic increase in incidence in patients under 50 years of age. The interaction between tumour and microbiome is recognised as central to the development, progression and response to treatment of colorectal cancer. Bacteria communicate with each other and with host cells (e.g. immune cells) via metabolic products, various lipids and extracellular vesicles (EVs; also outer membrane vesicles/OMVs). However, this information and its localisation in patient tissue cannot be obtained with modern 16S rRNA sequencing of the microbiome and the newer spatial transcriptomics. Within ColoBIOTA, we will develop additional methods to characterise the microbiome directly from intestinal tissue with the following aims 1) establishing the isolation and characterisation of microbiota-derived OMVs; 2) spatial analysis of the produced bacterial metabolites by in situ mass spectrometry; 3) acquisition of information on the co-localisation of metabolites and producing bacteria by fluorescence in situ hybridisation (FISH) after mass spectrometry (metaFISH). By characterising the colorectal cancer-associated microbiota using the above-mentioned methods, our multidisciplinary cooperation network, consisting of teams from the medical school OWL, the Faculty of Physics and the Faculty of Chemistry at Bielefeld University, as well as external partners from the Università degli Studi di Torino and the Technical University of Munich, will create the basis for understanding the interaction between tumour and microbiome in the context of colorectal carcinogenesis and to be able to use it therapeutically in the future.

Identification of neurophysiological biomarkers of social interaction for the optimisation of the diagnosis of autism spectrum disorders

Abstract:

The diagnosis of autism spectrum disorders (ASD) has increased significantly in recent years due to the popularity and relevance of the diagnosis. Up to now, this has been based primarily on clinical interviews with affected individuals and relatives as well as questionnaires. In adulthood, however, there are various problems, such as a lack of testimonials and a desirability bias. Particularly in the context of diagnosing people with intellectual impairments, but also in the case of female test subjects, further problems arise, such as the limited possibility of taking a personal history and possibly atypical symptoms. In recent years, there have been increasing attempts to collect neurophysiological biomarkers that could enable better, objectifiable diagnostics. Eye movements, heart rate variability, skin conductance and facial and pupillary mimicry are useful here, as these can provide indications of physical reactions in social interactions that can be objectively recorded. Furthermore, the diagnostics can open up the possibility of recording stress over a lifetime (adversity), which offers the possibility of counselling those affected with regard to further stress. In our project, we want to examine adults from the entire autism spectrum, i.e. both from the high-functioning range and with an additional intellectual disability, and compare them with people without ASD. We plan to investigate the above-mentioned physiological markers during social interaction tasks. Paradigms already established in the working groups will be used, such as an emotion recognition task. The results will serve as the basis for a broad-based clinical trial using machine learning (ML), possibly expanded to include additional biomarkers.

Prevalence and therapeutic management of climate anxiety in psychiatric care in Germany

Abstract:

The aim of the project is to take stock of new climate-associated forms of stress in
patients and hospital staff in outpatient and (partially) inpatient psychiatric care in Germany. Particular attention will be paid to the effects of climate change on mental health. In addition, the current significance of the topic of climate anxiety in the everyday treatment of psychiatric patients will be analysed. With regard to patients and hospital staff in (partial) inpatient and outpatient psychiatric care in Germany, the project will investigate the following three questions: (1) How frequently do the new forms of stress under the influence of climate change occur in the study population? (2) How pronounced is the awareness and knowledge of climate change and its consequences, as well as the extent to which individuals are affected? (3) How and in what form are new forms of stress associated with climate change taken into account in the treatment of patients? All three questions will be analysed with regard to various diversity characteristics and intersectionality, i.e. the interaction of several categories of difference. The research project consists of 6 work packages: WP 1: Systematic literature review, WP 2: Development of the online questionnaire, WP 3: Pretest of the questionnaire, WP 4: Quantitative data analysis of DGPPN members and patients in outpatient and (partial) inpatient psychiatric care, WP 5: Qualitative expert interviews from the field of psychiatric-psychotherapeutic complex treatment, WP 6: Dissemination of WP 4 and WP 5 in scientific peer-reviewed journals. For the survey of patients in outpatient and (partial) inpatient psychiatric care and members of the DGPPN (> 11,000 members), a sample size of around n = 550 is envisaged based on an a priori power analysis (WP 4).

Amyotrophic lateral sclerosis: diagnosis using whole genome sequencing and machine learning

Abstract:

In the planned co-operation project, patients with a suspected diagnosis of amyotrophic lateral sclerosis (ALS) will be examined. Whole genome sequencing will be performed and analysed using an AI algorithm. The methodology is compared with the clinical diagnosis according to the current gold standard. The sensitivity and specificity of the diagnostic procedure is calculated and compared with the comparative values of previous diagnostic standards such as the Gold Coast and El Escorial criteria as well as diagnostic laboratory values such as neurofilament light chains. In addition, we will analyse the whole genomes for the genes that have the greatest influence on the prediction of ALS. We will also analyse the data separately by patient gender in order to identify any gender differences. This project is the first prospective study to test AI-supported genome analysis in the diagnosis of ALS. The study can therefore potentially change the diagnostic process in the long term, lead to an earlier diagnosis of ALS and thus make a big difference for future ALS patients. In addition, the study offers very good opportunities for further research, as we are collecting extensive data that can be analysed for further questions if necessary. This project also promotes networking between the Department of Neurology and the participating centres at Bielefeld University (Omics Core Facility NGS Unit, MedFak OWL & CeBiTec - Center for Biotechnology and Faculty of Technology).

Gender differences in the modulation of immune and inflammatory networks by etoricoxib, a mechanistic and exploratory pilot study

Abstracts:

Chronic inflammatory pain is one of the most common health problems and affects more women than men. It leads to an impairment of quality of life and participation and causes considerable economic costs. Non-steroidal anti-inflammatory drugs (NSAIDs) are generally used as analgesics to treat chronic pain. However, there is a high inter-individual variability in the effect of NSAIDs and in the side effects that occur. The underlying
mechanisms of the inter-individual variability in the response to NSAIDs have not been clarified. Although women are more frequently affected by chronic pain, the role of gender as a potential factor influencing the analgesic efficacy of NSAIDs has not been systematically investigated. In this pilot project, we pursue the hypothesis that there are molecular differences in the anti-inflammatory effect of etoricoxib between women and men that may lead to variability in analgesic efficacy. We will use endotoxin-stimulated human immune cells as a model for inflammatory pain and employ modern high-resolution single-cell transcriptomics (scRNA-seq) to investigate gender-specific differences in the molecular response. Our interdisciplinary collaboration addresses the following overarching goals: (1) to strengthen the research focus of the medical school OWL in the areas of gender-sensitive medicine and brain - impairment - participation; (2) to investigate for the first time the influence of gender in the context of NSAID therapy in a targeted manner to pave the way for gender-specific therapeutic interventions; (3) to advance personalised NSAID therapy; and (4) to provide a solid foundation for a third-party funded follow-up project that can guide the career development of three young female scientists.
therapy and (4) to provide the groundwork for externally funded follow-up studies as a critical next step in the career advancement of these three early-stage investigators.

Genetic differences in sex hormone receptors in patients with atrial fibrillation

Abstract:

The GENE-AF project aims to investigate sex-specific genetic variants in sex hormone receptor genes in patients with atrial fibrillation (AF) compared to a control group without cardiac disease. The study investigates how frequently corresponding genetic variants occur and analyses their molecular biological properties using cell culture models. A particular focus is on the influence of ion channels, membrane and electrophysiological properties of the variants identified in the study as well as changes in protein localisation and concentrations. In addition, the relationship between sex hormone levels and the occurrence of VHF will be analysed. The aim of the study is to better understand the complex aetiology of AF, in particular the gender-specific role of sex hormones. Primary endpoints are the prevalence of genetic variants in sex hormone receptor genes and atypical cellular signalling in AF patients. Secondary endpoints include the analysis of sex hormone levels and the development of in vitro models for molecular biological and electrophysiological investigations. The pilot study is prospective, unblinded and non-randomised, planned with 40 patients, including 30 with VHF and 10 as a control group of equal gender parity. Recruitment will take place at the University Clinic for Cardiology and Internal Intensive Care Medicine, with special consideration being given to postmenopausal AF women and young male patients (>30 years). The genetic analysis is carried out by means of complete exome sequencing at the OMICS Core Facility. Subsequently, potential new gene variants will be analysed in vitro in human cell culture models. In summary, the results of the GENE-AF study will contribute to a better classification of gender-specific factors in VHF and create the basis for further patient-specific treatment methods and basic research.

Elucidation of the role of septin GTP phases in renal mitochondrial dynamics during cadmium-induced stress

Abstracts:

Exposure to low-dose cadmium (Cd), a recognised health risk, is associated with chronic renal damage and carcinogenesis. Cd accumulates in the proximal renal tubules and causes progressive tubular apoptosis or necrosis upon acute exposure, while chronic exposure leads to fibrosis and ultimately renal failure. While mitochondrial dysfunction and mitophagy play a role in Cd-induced toxicity, the exact mechanism of removal of damaged mitochondria remains unclear. Mitochondrial fission, or fission, the precursor to mitophagy, involves septins, a family of cytoskeletal GTPases involved in organelle dynamics. New evidence suggests that septins are located near mitochondrial fission sites, with septin 2 controlling the positioning of dynamin-related protein 1, a key mediator of the process, in epithelial cells. However, the role of septins in the kidney, particularly under Cdinduced stress, remains largely unexplored. This study elucidates septin dynamics in cadmium toxicity using WKPT-0293 Cl.2 cells, a proximal tubule cell line sensitive to Cd exposure. Preliminary results show an increase in septin abundance and mitochondrial fission after cadmium treatment (5 μM CdCl₂, 1-24 hours). To clarify septin function under toxic stress, we will assess septin polymerisation, spatial distribution and mitochondrial interactions using multiplex imaging. Functional studies with siRNA-mediated septin knockdown will determine its necessity for the initiation of mitochondrial fission. In addition, a mitophagy-recognition model using mt-mKeima will investigate the septin contribution to organelle clearance. This work fills critical gaps in the understanding of cadmium-induced nephrotoxicity by linking septins to mitochondrial dynamics and providing potential therapeutic targets to alleviate cadmium-related kidney disease.

Use of gaze tracking to improve the diagnosis of attention deficit hyperactivity disorder (ADHD) in adults with disorders of intelligence development (SIE)

Abstract:

The human physiological behaviour is determined to the 24-hour day-night cycle. Intracellular circadian clocks of the suprachiasmatic nucleus (SCN) are the pacemaker of this rhythm with input of photoreceptors. A disruption or misalignment of the circadian clocks leads to severe impact on human health and places an enormous financial burden on the German healthcare system. Pharmacological compounds that modulate the cellular clocks may serve here as a potential therapy. The human cryptochrome 1 (hsCRY1) is a key component of the circadian clock and therefore a suitable target for therapies. Recently, the photo-pharmacological compound GO1323 have been developed that targets hsCRY1. The compound can be reversibly activated and deactivated by light thereby modulating the cellular clock. The mechanism of GO1323 on hsCRY1 have not been fully revealed yet and structural studies on the compound were only conducted on cryptochrome1 of mice. In this project, we will investigate the mechanism of GO1323 and a new synthesised compound with improved photophysical properties on hsCRY1 using infrared difference spectroscopy, cryogenic electron microscopy and fluorescence microscopy. Combining structural and human cell experiments on hsCRY1, will provide a more profound insight into the mechanism of (photo-)pharmacological compounds with implication for future pharmacological therapies regarding hsCRY1 in clinical research.

Spatial analysis of the tumour microenvironment and immune cell diversity using multiplex analysis of biomarkers in lung and pancreatic cancer.

Abstracts:

Lung and pancreatic cancers continue to have high incidence and mortality within the EU according to recent reports from the European Society for Medical Oncology (ESMO). The complex tumour microenvironment (TME) plays a crucial role in the development and evasion of the immune system of these lethal malignancies. The latest techniques in metabolomics and lipidomics provide unique insights into the biochemical changes within TMEs that promote tumour growth and suppress immune responses. To perform a comprehensive analysis of the metabolome and lipidome in tumours and their tumour (immune) microenvironment (T(I)ME), matrix-assisted laser desorption/ionisation (MALDI) imaging will be combined with MALDI immunohistochemistry (IHC). The resulting molecular maps of the tissue should enable the identification of specific biomarkers that reveal the metabolic adaptations of tumours and changes in the lipid composition and influence the function of immune cells. This research approach integrates spatially resolved molecular imaging with high-throughput analytical methods and enables metabolic signatures to be correlated with immune cells and tumour progression. Another important aspect of this project is the methodological and analytical establishment of MALDI-IHC at the medical school OWL, which can also be used for further research into other chronic diseases. The current state of research points to metabolic and lipidomic changes in tumours and TME, which are associated with the aggressiveness of the tumour and the modulation of the immune response. Their exploration may identify new biomarkers that can be used for early diagnosis, prognostics and targeted therapy strategies for these cancer entities. This research emphasises the value of MALDI-Imaging and MALDI-IHC as innovative platforms for biomarker discovery within the metabolically active and immunologically complex TME.

Mechanism of action of photopharmacological substances on the human circadian rhythm

Abstract:

Human physiological behaviour is determined by the 24-hour day-night cycle. Intracellular circadian clocks of the suprachiasmatic nucleus (SCN) involving photoreceptors are the pacemakers of this rhythm. A disruption or incorrect adaptation of the circadian clocks leads to serious health effects and represents an enormous financial burden for the German healthcare system. Pharmacological agents that modulate the cellular clocks
could represent a therapy here. Human cryptochrome 1 (hsCRY1) is a central component of the circadian clock and is therefore a suitable target for therapies. Recently, the photo-pharmacological agent GO1323 was developed that targets hsCRY1. The compound can be reversibly activated and deactivated using light, enabling precise and non-invasive modulation of the circadian clock. The mechanism of action of GO1323 on hsCRY1 has not yet
been fully elucidated and structural studies on the compound have only been performed on cryptochrome 1 from mice. In this project, we will investigate the mechanism of action of GO1323 as well as that of a new synthetic compound with better photo-physical properties on hsCRY1 using infrared difference spectroscopy, cryo-electron microscopy and fluorescence microscopy. The combination of structural and human cell experiments on hsCRY1 will provide a better insight into the mechanism of action of (photo)pharmacological agents, which will have an impact on future pharmacological therapies targeting hsCRY1 in clinical research.

Nano-/microplastics (NMP) and bacteria: Modelling the effect of NMP on gut microbiota-host interaction

Abstracts:

Nano/micro/plastic particles (NMPs) are widely present in the environment, food, beverages and cosmetics. The increasing and reported human exposure to NMPs raises questions about potential risks to human health. The presence of NMPs in human tissues and organs and possible adverse effects on the healthy gut microbiota and host following ingestion of NMPs have been reported. Recently, environmental factors (e.g. working in the plastics industry) have been shown to increase the risk of colorectal cancer. Colorectal cancer is the third most common cancer in Germany, and the interaction between tumour and microbiota is of great importance for its development and therapeutic success. However, the mechanisms behind this interaction are not yet fully understood and the extent to which NMPs can influence the microbiota and colorectal cancer development is largely unknown. Therefore, further research is needed to better understand how NMPs affect the human gut, as the gut microbiota is critical not only for susceptibility to colorectal cancer, but also for metabolism and immunity. By developing methods to characterise NMP mixtures (Aim 1) and analysing the effects of NMPs on the microbiota in in vitro co-cultures and invertebrate models (Aim 2), PlastBac will enable further studies on the effects of NMPs on colorectal cancer and other chronic diseases. This will significantly contribute to our knowledge of the effects of NMPs on human health and colorectal carcinogenesis.

Effect of apolipoprotein AIV on platelet activation and the lipidome in healthy volunteers postprandially

Abstracts:

Apolipoprotein AIV (apo AIV) is a plasma protein that is present both in a lipid-free form and bound to lipoprotein particles. It is mainly synthesised in the small intestine during fat absorption and is thus involved in lipid metabolism and transport. Interestingly, recent findings have shown additional functions of apo AIV such as anti-inflammatory, antidiabetic and antithrombotic effects. By binding to the platelet albJ33 receptor, Apo AIV promotes the inhibition of platelet aggregation and thrombosis, attenuates postprandial platelet hyperactivity and therefore suggests protective properties against cardiovascular disease. In particular, activated platelets are present in atherosclerosis and dyslipidaemia, which often lead to thrombus formation and myocardial infarction in patients with acute coronary syndrome (ACS). In addition, changes in the platelet lipidome in activated platelets and significantly altered lipids were found in patients with acute coronary syndrome (ACS). Since the antithrombotic properties of Apo AIV in humans have not been fully explored, the proposed study aims to investigate the effect of Apo AIV on platelet activation and lipidome in healthy volunteers consuming a defined high-fat diet compared to the nuchal state. This study contributed to the understanding of the effects of apo AIV on platelet function/activation and the lipidome in humans and could lead to the development of new therapeutics to prevent and protect against cardiovascular disease. The following research work will therefore concentrate on investigating the antithrombotic effect of apo AIV.
and in the ACS patients with Ml.

Calcification and lesion assessment for risk detection in tissues

Abstract:

More than 235 million people worldwide and 7% of people in Germany are affected by the chronic disease peripheral arterial occlusive disease (PAD) as a manifestation of systemic atherosclerosis (ASCVD) [1,2]. In classic population studies such as the Framingham Study, a twice higher prevalence was reported in men compared to women, while more recent epidemiological studies indicate a higher incidence in women. This becomes particularly clear when income is taken into account as an influencing factor [3]. PAD of the lower extremities leads to critical ischaemia and amputation and is a strong predictor of cardiovascular and cerebrovascular events and mortality even in the asymptomatic stage [4, 6]. Despite its relevance to overall health, PAD is the most frequently unrecognised of all ASCVD manifestations. As a consequence, the necessary intensive therapy is not provided and the potential of secondary prevention remains underutilised [6]. Diabetes and obesity increase the risk of PAD two- to four-fold
and the presence of PAD in people with diabetes quadruples the risk of amputation and death [7,8]. Although a paradigm shift in diabetes care away from a purely glucocentric approach to cardiorenal organ protection in people at high risk of ASCVD was heralded ten years ago [9], there is still a relevant gap in care that justifies the need for new methods to identify at-risk patients in order to consistently implement more intensive treatment strategies and thus improve the long-term health outcomes of people with diabetes [10].

Spectroscopy as the key to modern diagnostics of inflammation

Abstract:

The aim of this application is to establish an interdisciplinary, translational research cooperation at Bielefeld University that combines scientific and medical expertise for research in the field of inflammation diagnostics. The aim is to further develop suitable complementary spectroscopic and spectrometric methods in conjunction with mathematical, statistical and algorithm-based evaluation methods for the diagnosis and clarification of medical issues and to bring them into clinical application. Thanks to the combined expertise and successful preliminary work of the applicants, a DFG Research Training Group application will be submitted within the funding period. Conditions of severe systemic inflammation such as sepsis are characterised by a pathophysiology that is still largely unknown. Mortality is high and the prognosis cannot be made with sufficient precision and speed using current diagnostic methods. Chronic inflammation is decisive for the extent of damage to tissues and organs in the majority of chronic diseases, but is largely misunderstood and therefore inadequately treatable. Future personalised medicine faces the challenge of diagnosing and differentiating the various stages and pathophysiological processes in order to be able to provide individual and targeted treatment. Spectroscopic diagnostics based on Raman scattering, infrared absorption and other spectroscopic methods have the potential to achieve this. Based on initial results, we assume that pattern recognition in longitudinal blood tests and cell experiments will enable us to characterise and classify patients individually with much greater precision in terms of the stage of the process, causes, prognosis, complications and therapeutic options. This development opens up innovative therapeutic approaches and will contribute to future precision medicine. The aim of the CLARITi project is to establish calcification markers in the blood as predictors of PAD. The identification of patients at risk allows early treatment before relevant ischaemia impairs vascular health. We plan to measure calcification markers in the atherosclerotic plaque, in the immediate vicinity of the plaque and in the peripheral bloodstream. Proof-of-concept studies have already successfully identified calcification-associated markers using mass spectrometry methods and detected these markers in the peripheral blood of PAD patients. Combining these findings in validation experiments will allow a differentiated graduation of atherosclerotic plaques. Lipidomics analyses carried out at the Bielefeld campus complement the range of methods and thus increase the chance of gaining relevant knowledge. CLARITi is to form the crystallisation nucleus for a DFG research group dedicated to the identification of biomarker analysis, early diagnosis and interventional therapy of cerebro/cardiovascular diseases.

Inclusive child health in OWL

Abstract:

The research project "Inclusive Child Health in OWL (KINO)" is dedicated to improving the medical and psychosocial care of children and adolescents with disabilities in the Ostwestfalen-Lippe (OWL) region. The aim is to carry out a comprehensive analysis of the current situation and needs in order to identify gaps in care and structural deficits. The transition from paediatric to adult medicine poses a particular challenge for those affected and their families, as specialised care structures are often insufficiently networked or non-existent. Based on the results of the analysis, innovative care approaches are to be developed in a targeted manner. These include a new Bielefeld transition programme that structures the transition between different care sectors and improves medical, therapeutic and social support. In addition, a pilot model for integrated care is being designed to strengthen interdisciplinary cooperation between doctors, therapists, carers and social services. A particular focus is on the use of new technologies, including telemedicine solutions, guidance systems and AI-supported assistance systems, which are intended to improve access to and the quality of care. The project combines expertise from the fields of medicine, health sciences, psychology and technology and follows a participatory approach in which those affected and their families are actively integrated into the design of new care models. Through close scientific monitoring and evaluation, the Bielefeld model for inclusive child health should serve as a blueprint for other regions and set national and international standards in the care of children and young people with disabilities in the long term.