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Prof. Dr. Primo Leo Schär

Department of Biomedicine
Profiles & Affiliations

Projects & Collaborations

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Air Pollution and Effects on Lung Functional Development and Respiratory Morbidity in At-Risk Infants

Research Project  | 4 Project Members

BACKGROUND AND RATIONALE: This is a direct continuation of SNF 182871/1, which investigated the impact of early-childhood environmental factors on lung functional growth and consequences for later respiratory morbidity in healthy term infants. We previously demonstrated that even low-level air pollution exposure during pregnancy and early childhood is associated with impaired lung functional growth in infancy and early childhood. Although the mechanisms are still unclear, they could be related to lung functional growth deficits or remodeling of the lung due to changes in the intrauterine environment. Air pollution is known to induce oxidative stress response and related autophagy and cellular senescence mechanisms, potentially playing a role in pollution-related lung pathology and in remodeling. As novel preliminary evidence in SNF 182871/1, we recently found that, in the cord blood of human infants, autophagy-related biomarkers are correlated with remodeling biomarkers. We also found that air pollution exposure during pregnancy is associated with biomarkers of autophagy and remodeling in the cord blood of healthy term infants. Interestingly, these mechanisms also play an important role in fetal development and preterm birth, and may thus theoretically contribute to the susceptibility of infants-and particularly preterm infants-to oxidative stress and air pollution effects. Indeed, as first evidence from SNF 182871/1, we also found an enhanced impact of air pollutants on lung function impairment of preterm infants. Furthermore, our own preliminary human data show that markers of autophagy, and remodeling already have significant differences between the cord blood of preterm infants compared to term infants at birth prior to early postnatal injury. Bringing this together, we hypothesize that the interaction of oxidative stress response, autophagy and remodeling could be a key mechanism involved in the complex host-environment interaction determining lung functional growth and related respiratory morbidity. Moreover, this response could be different in infants at risk for chronic respiratory symptoms, such preterm infants, infants born from asthmatic mothers or infants exposed to high levels of air pollution during pregnancy. OVERALL OBJECTIVES: We aim to expand the ongoing BILD cohort of (i) term infants with two risk subgroups, (ii) infants born preterm, and (iii) infants born to asthmatic mothers, and we will investigate the differences in response to prenatal air pollution in relation to the above key mechanisms. SPECIFIC AIMS: In comparison to healthy term infants, we will investigate in study phase 1, (i) whether the increased susceptibility of infants to prenatal air pollution in these three risk groups is related to differences in markers of oxidative stress response, autophagy, and remodeling in cord blood and in study phase 2, (ii) whether these pollution-related cord blood profiles are correlated to lung functional development and subsequent symptoms in the first year of life (primary outcomes) and at school age (secondary outcomes). We will replicate these findings in other birth cohorts from collaborators (Germany, Australia) with comparable outcome measures. METHODS: In our prospective BILD birth cohort of 1000 unselected healthy term infants, 400 preterm infants, and 200 infants from asthmatic mothers we will (i) estimate indoor and outdoor air pollution exposure during pregnancy and in early infancy, (ii) assess family, obstetric and birth history, cord-molecular biomarkers (metabolomics, gene expression, proteins), and infant lung function shortly after birth (including exhalomics) and at 6 years of age, as well as respiratory symptoms in the first year of life and at school age. EXPECTED RESULTS AND IMPACT: We expect a 26.03.2021 18:35:26 Page - 14 - significant correlation between air pollution exposure and oxidative stress response and lung remodeling in newborns with effects on lung function and clinical outcomes, the latter effects enhanced in the risk groups. Particularly for these risk groups, today's air pollution may already result in lung remodeling and subsequent impaired lung functional growth even at this early stage of life. Since early-life lung functional impairment often persists until school age and even late adulthood, it is a previously described early-life risk factor known to be associated with asthma in children and chronic obstructive respiratory airway diseases in the elderly. Thus, early-life environmental injury has a potentially very relevant impact on future global respiratory health, with unpredictable costs. We are one of the first groups to look into the impact of these air-pollution-induced mechanisms on oxidative stress response and lung remodeling, subsequent impairment of lung functional growth, and resulting human lung disease. Better understanding of these mechanisms might help the development of preventative and therapeutic strategies, particularly for at-risk infants.

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DNA Demethylation-Induced DNA Repair in Chromatin Regulation

Research Project  | 1 Project Members

The concerted action of transcription factors, chromatin organizers, histone and DNA modifiers and DNA metabolic processes creates structural and functional dynamics in chromatin, facilitating the differentiation of stable gene expression programs that define cell identities. While this is accepted, insight into how the different layers of genome regulation co-operate has remained poor. The discovery of active DNA demethylation, which can occur through a process of 5mC oxidation by TET proteins and replacement of the oxidized 5mC by TDG-dependent base excision repair (BER), has added another piece to the puzzle. We contributed to and followed up on this discovery to delineate the mode of action of TET-TDG-BER-mediated DNA demethylation and to investigate its biological function. This revealed that certain genomic loci undergo continuous DNA repair-mediated demethylation, providing a conceptual framework to link DNA demethylation with nucleosomal dynamics. DNA repair processes inherently have dynamic properties as they entail opening, editing and re-synthesizing DNA, events that involve signaling to chromatin. Indeed, transcriptional activation and cellular reprogramming have been associated with the formation of DNA single strand-breaks (SSBs) and the engagement of BER proteins (XRCC1, PAPR1), consistent with DNA SSB formation and repair contributing to the establishment and/or maintenance of a permissive chromatin state. Prompted by such observations, we investigated the hypothesis that DNA demethylation operates to target DNA SSBs to genomic sites where epigenetic plasticity is to be established or maintained. This project is a refined approach to address the following hypothesis. TET-TDG-BER mediated DNA demethylation plays an active role in regulating chromatin accessibility at enhancers and gene promoters. Changes in chromatin accessibility are achieved (i) by modulation of linker histone H1 association, whereby DNA repair activity associated with DNA demethylation (NPM1, NPM3, PARP) plays an active role and facilitates the establishment of enhancer-promoter loops, and (ii) by changes in histone modification, facilitated by TET-TDG dependent modulation of MLL and PRC2 activities. Research towards the following objectives is pursued to address this hypothesis Objective 1: Deciphering the role of nucleophosmin in TET-TDG-dependent regulation of chromatin accessibility. Objective 2: Deciphering the role of TET-TDG dependent DNA demethylation in the regulation of MLL and PRC2 histone methyltransferase complexes.

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Impact of mobile communication signals on the regulation of neural differentiation

Research Project  | 4 Project Members

Our project aims at studying possible effects of radiofrequency electromagnetic fields (RF-EMF) on neuronal differentiation and related cellular pathways known to be involved in neurodegeneration and associated diseases. Focusing on pathways playing a role in neuronal differentiation and degeneration, we will investigate RF-EMF effects on distinct neuronal cell populations before and during differentiation and identify molecular pathways involved in a hypothesis-free genomic approach as well as in a hypothesis-driven approach. These goals will be achieved by applying cell culture-based experimentations including neuron-like and neuronal stem/progenitor cells. Progression of differentiation and phenotypic characterization will be assessed by fluorescence microscopy of stem cell and neuronal markers combined with high-content analysis and evaluation of morphology (i.e. neurite outgrowth). These analyses will be complemented by the assessment of key players of cellular pathways (e.g. the ERK/MAP-K, PI3-K/Akt, Wnt/β-catenin) underlying the morphological changes such as neurite outgrowth in a quantitative manner (e.g. by Western blotting and FRET-biosensor). Mitochondrial dysfunction during neurodegeneration was shown to increase the production of reactive oxygen species (ROS). Oxidative stress is a frequent early condition in the pathogenesis of neurodegenerative diseases, is often observed in cells upon EMF exposure and has an evident potential to compromise genetic as well as epigenetic stability. Mitochondrial integrity, an important indicator of neuronal aging and degeneration will be investigated quantitatively. To assess the impact of RF-EMF exposure on the composition and behavior of the differentiating neural cell population, gene expression profiling (transcriptome) of single cells before and after differentiation will be performed. Cluster analysis of gene expression profiles will describe the dynamics of the cell population and potentially result in the identification of target regions with altered epigenetic modifications. Target-specific quantitation of DNA methylation and histone modifications at regulatory elements (promoter, enhancer) of identified genes, markers of neural stem cell and the neuronal lineage will be analyzed by pyrosequencing of bisulfite-converted DNA and by chromatin immunoprecipitation (ChIP). This project will provide a significant and critical insight into the adverse effects of exposure to modulated RF-EMF as used for mobile communication (GSM) on signaling cascades and physiology as well as on morphological and epigenetic characteristics of neural cells in vitro .

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Pilot Study PIOMIC - Wound Healing Models

Research Project  | 2 Project Members

The goal of this research proposal is to establish a cell culture-based experimental model system in a hypothesis-driven and explorative manner, which can be used for future evaluation of therapeutic variables and for pinpointing and investigating treatment-influenced biological processes. This information will provide the scientific rationale for the therapeutic application of the combined light/PM-ELF-MF exposure. First and foremost, the proposed research shall: clarify if the combined PM-ELF-MF/light exposure is manifesting in a biological response in cultured cells, focusing on the proliferation, migration and angiogenesis of fibroblasts, endothelial cells and keratinocytes estimate the contribution of waveforms to promote the biological effect by varying and/or excluding PM-ELF-MF and light signals during exposure elucidate redundant, additive or synergistic effects of the combined exposure approach compared to the separate exposure to either light or PM-ELF-MF reveal whether the enhanced healing process is promoted by affecting distinct cell types or rather by collective response of involved cells establish experimental conditions with solid response in order to tackle molecular pathways and mechanisms in more detail.

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Sub-cellular targeting microscopy - Signaling in Development and Oncology

Research Project  | 6 Project Members

In the past decade, research in development and oncology has uncovered an impressive number of relevant signaling pathways. While a qualitative understanding of signals, and their connection to cellular outputs has been established, plasticity and feedback of signaling networks remain obscured. A better understanding of dynamic and locally constrained signaling events driving organ development and disease progression requires access to refined subcellular probe detection. The availability of optogenetic and chemical biology tools provides novel opportunities, but requires dedicated microscopy equiment. For this reason, six projects at the Department of Biomedicine (DBM) and the Biocenter (BC) of the Univerisity of Basel i) localized lipid signaling in disease (M. Wymann, DBM); ii) dynamic subcellular Wnt/b-catenin signaling in epithelial mesenchymal transition (G. Christofori, DBM); iii) DNA dynamics and confined epigenetic plasticity (P. Schär, DBM); iv) real-time monitoring of Sonic Hedgehog and Bone Morphogenetic Protein gradients in limb buds (R. Zeller, DBM); v) ultrastructural analysis of neuronal stem cell control (V. Taylor, DBM); and vi) molecular mechanisms determining the development of vascular networks (M. Affolter, BC), illustrate the need of the requested "subcellular targeting microscopy" equipment. The core of the platform is a highly sensitive microlens-enhanced spinning disk microscope linked to FRAP, ablation, and multiple excitation laser lines, and an integrated TIRF module to monitor plasma membrane events. Through its integration into the BioOptics core facility at the DBM, the subcellular targeting platform will be accessible to >500 regional researchers at the University of Basel, DBM, FMI, D-BSSE, Fachhochschule, etc. An image storage and analysis pipeline with remote user access capabilitiy is in place, to allow seamless operation and output. The requested equipment will allow the use of genetically encoded opto-genetic proteins, proteins tagged for reactivity with chemical inducers of dimerisation (CIDs), and the possibility to perform FRAP/TIRF and FRAP/confocal microscopy, and will greatly enhance the possibilities to manipulate and track subcellular localization of target proteins. The insights gained by these experimental approaches will be critical for a better understanding of dynamic biological processes, and will spur the design of innovative therapeutic approaches to counteract resistance mechanisms in oncology.