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Prof. Dr. Mihaela Zavolan

Department Biozentrum
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Projects & Collaborations

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SIMBioData: Standardized integration of multi-omics biomedical data

Research Project  | 2 Project Members

As technological advances enable the collection of vast datasets of biomedical measurements, many ongoing studies attempt to decipher various aspects of human health from such data. Although the focus has been primarily on genetic information, other data modalities, such as the abundances of RNAs and proteins within cells and tissues, relate more directly to phenotypes. However, these latter modalities raise significantly more data analysis challenges, and so far, the emphasis in large consortia has been almost exclusively on data production, curation and storage. Efforts to standardize analysis methods so as to allow application on a large scale without the need for subjective choices, are virtually nonexistent. Moreover, while measures have been put in place to ensure that the data generated in scientific studies satisfies the FAIR principles, FAIRification of methods does not help in addressing issues of data quality, internal consistency, and interpretability of analysis outputs. We propose that to really harness the potential of the wealth of omics data for biomedical research, it is essential to establish a standardized, sustainable and evolvable method infrastructure for extracting biophysically-meaningful quantities and underlying regulatory information. In particular, only by providing standardized methods that extract biophysically-meaningful quantities in a transparent manner, will it become possible to quantitatively compare and integrate results from omics data across different modalities and experimental approaches. In addition, we feel that our project will provide an ideal prototype for the analysis component of the SwissBioData initiative, which is scheduled to start after the completion of our project.

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NCCR phase 3, 2.9 Role of RNA oxidation in muscle aging

Research Project  | 3 Project Members

RNA - the fundament of life: The origin of life on earth most likely relied on ribonucleic acid (RNA), and still today this versatile linear polymer is the central molecule in living cells. It can store and regulate genetic information and have enzymatic activity. Whereas less than 2% of the human genome codes for protein, up to 95% of it is transcribed into RNA, documenting the existence of an overwhelmingly large number of so far neglected non-coding (nc)RNAs with probably important functions. The discovery of small ncRNAs put research on RNA-mediated gene regulation and its potential for applications in medicine and biotechnology definitively on the center stage of the life sciences, but many physiologically important levels of RNA-based gene regulation still remain to be discovered and deciphered. Basic research on RNA biology therefore greatly advances our understanding of the molecular underpinnings of life, a prerequisite for understanding the molecular causes of disease. Indeed, research building on these new findings in RNA biology has already resulted in first therapeutic and diagnostic applications in medicine, and many more are expected to follow.Goals of the NCCR RNA & Disease: Research on RNA-related topics is carried out in a number of academic and industrial laboratories in Switzerland. A disproportionately large number of these research groups are internationally renowned for their outstanding work, in spite of the fact that individual laboratories often lack critical mass in addressing specific research problems with a comprehensive approach. A coordinated, interdisciplinary initiative that promotes visibility and facilitates rapid transition of new findings into medical applications does not yet exist. The NCCR initiative RNA & Disease therefore aims at consolidating and reinforcing the already strong position of Switzerland in RNA research. Our main goals are: -Advancing our understanding of RNA processing and surveillance mechanisms involved in global regulation of messenger and non-coding RNA. -Identification of disease mechanisms resulting from aberrant RNA function and development of possible therapeutic approaches for their cure. -Establishing a Swiss RNA research cluster that enhances and consolidates the role of Switzerland as an international leader in RNA biology. Projected research activities: Research to achieve the first two goals is organized in three interlaced work packages (WPs) consisting of collaborative multidisciplinary projects: WP1 is aimed at investigating disease-associated alterations in specific ncRNA species and elucidating their biological functions and molecular mechanisms, WP2 will advance our current understanding of RNA metabolism, its regulation in health and disease, and the development of antisense-based therapeutic approaches, and WP3 focuses on the dissection of ribosome biogenesis pathways to reveal disease-associated errors, and on ncRNA-mediated regulation of translation. The NCCR RNA & Disease will be jointly hosted by the University of Bern and the ETH Zürich, with additional participating teams located in Basel (FMI and Biozentrum) and Lausanne (EPFL).Added value for the Swiss scientific landscape and society: The NCCR RNA & Disease will provide a platform for high-quality, interdisciplinary education of students and postdocs in the rapidly growing field of RNA biology, thereby meeting the rising demand of the Swiss pharmaceutical and biotech industry for scientists with such specific knowledge. Our initiative will structure existing activities as well as initiate new collaborative projects among 16 academic labs of the consortium and beyond, with the long-term strategy to gradually develop the results of basic research towards medical and pharmaceutical applications. Moreover, the planned establishment of new assistant professorships and financial support for additional up to 6 junior groups will significantly enhance innovative RNA research in Switzerland and ensure its perennity. We expect that novel disease-related, therapeutically relevant RNA targets will be discovered, offering opportunities for industrial partners or for launching start-up companies. Simultaneously, the visibility of this important field at the frontier of modern life sciences will increase and help Switzerland to promote its reputation of a lighthouse for groundbreaking science.

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NCCR phase 3, 3.10 Ribosomal protein paralog-dependent disease mechanisms

Research Project  | 3 Project Members

RNA - the fundament of life: The origin of life on earth most likely relied on ribonucleic acid (RNA), and still today this versatile linear polymer is the central molecule in living cells. It can store and regulate genetic information and have enzymatic activity. Whereas less than 2% of the human genome codes for protein, up to 95% of it is transcribed into RNA, documenting the existence of an overwhelmingly large number of so far neglected non-coding (nc)RNAs with probably important functions. The discovery of small ncRNAs put research on RNA-mediated gene regulation and its potential for applications in medicine and biotechnology definitively on the center stage of the life sciences, but many physiologically important levels of RNA-based gene regulation still remain to be discovered and deciphered. Basic research on RNA biology therefore greatly advances our understanding of the molecular underpinnings of life, a prerequisite for understanding the molecular causes of disease. Indeed, research building on these new findings in RNA biology has already resulted in first therapeutic and diagnostic applications in medicine, and many more are expected to follow.Goals of the NCCR RNA & Disease: Research on RNA-related topics is carried out in a number of academic and industrial laboratories in Switzerland. A disproportionately large number of these research groups are internationally renowned for their outstanding work, in spite of the fact that individual laboratories often lack critical mass in addressing specific research problems with a comprehensive approach. A coordinated, interdisciplinary initiative that promotes visibility and facilitates rapid transition of new findings into medical applications does not yet exist. The NCCR initiative RNA & Disease therefore aims at consolidating and reinforcing the already strong position of Switzerland in RNA research. Our main goals are: -Advancing our understanding of RNA processing and surveillance mechanisms involved in global regulation of messenger and non-coding RNA. -Identification of disease mechanisms resulting from aberrant RNA function and development of possible therapeutic approaches for their cure. -Establishing a Swiss RNA research cluster that enhances and consolidates the role of Switzerland as an international leader in RNA biology. Projected research activities: Research to achieve the first two goals is organized in three interlaced work packages (WPs) consisting of collaborative multidisciplinary projects: WP1 is aimed at investigating disease-associated alterations in specific ncRNA species and elucidating their biological functions and molecular mechanisms, WP2 will advance our current understanding of RNA metabolism, its regulation in health and disease, and the development of antisense-based therapeutic approaches, and WP3 focuses on the dissection of ribosome biogenesis pathways to reveal disease-associated errors, and on ncRNA-mediated regulation of translation. The NCCR RNA & Disease will be jointly hosted by the University of Bern and the ETH Zürich, with additional participating teams located in Basel (FMI and Biozentrum) and Lausanne (EPFL).Added value for the Swiss scientific landscape and society: The NCCR RNA & Disease will provide a platform for high-quality, interdisciplinary education of students and postdocs in the rapidly growing field of RNA biology, thereby meeting the rising demand of the Swiss pharmaceutical and biotech industry for scientists with such specific knowledge. Our initiative will structure existing activities as well as initiate new collaborative projects among 16 academic labs of the consortium and beyond, with the long-term strategy to gradually develop the results of basic research towards medical and pharmaceutical applications. Moreover, the planned establishment of new assistant professorships and financial support for additional up to 6 junior groups will significantly enhance innovative RNA research in Switzerland and ensure its perennity. We expect that novel disease-related, therapeutically relevant RNA targets will be discovered, offering opportunities for industrial partners or for launching start-up companies. Simultaneously, the visibility of this important field at the frontier of modern life sciences will increase and help Switzerland to promote its reputation of a lighthouse for groundbreaking science.

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NCCR phase 3, Platform Basel Next Generation Sequencing Bioinformatics

Research Project  | 2 Project Members

RNA - the fundament of life: The origin of life on earth most likely relied on ribonucleic acid (RNA), and still today this versatile linear polymer is the central molecule in living cells. It can store and regulate genetic information and have enzymatic activity. Whereas less than 2% of the human genome codes for protein, up to 95% of it is transcribed into RNA, documenting the existence of an overwhelmingly large number of so far neglected non-coding (nc)RNAs with probably important functions. The discovery of small ncRNAs put research on RNA-mediated gene regulation and its potential for applications in medicine and biotechnology definitively on the center stage of the life sciences, but many physiologically important levels of RNA-based gene regulation still remain to be discovered and deciphered. Basic research on RNA biology therefore greatly advances our understanding of the molecular underpinnings of life, a prerequisite for understanding the molecular causes of disease. Indeed, research building on these new findings in RNA biology has already resulted in first therapeutic and diagnostic applications in medicine, and many more are expected to follow.Goals of the NCCR RNA & Disease: Research on RNA-related topics is carried out in a number of academic and industrial laboratories in Switzerland. A disproportionately large number of these research groups are internationally renowned for their outstanding work, in spite of the fact that individual laboratories often lack critical mass in addressing specific research problems with a comprehensive approach. A coordinated, interdisciplinary initiative that promotes visibility and facilitates rapid transition of new findings into medical applications does not yet exist. The NCCR initiative RNA & Disease therefore aims at consolidating and reinforcing the already strong position of Switzerland in RNA research. Our main goals are: -Advancing our understanding of RNA processing and surveillance mechanisms involved in global regulation of messenger and non-coding RNA. -Identification of disease mechanisms resulting from aberrant RNA function and development of possible therapeutic approaches for their cure. -Establishing a Swiss RNA research cluster that enhances and consolidates the role of Switzerland as an international leader in RNA biology. Projected research activities: Research to achieve the first two goals is organized in three interlaced work packages (WPs) consisting of collaborative multidisciplinary projects: WP1 is aimed at investigating disease-associated alterations in specific ncRNA species and elucidating their biological functions and molecular mechanisms, WP2 will advance our current understanding of RNA metabolism, its regulation in health and disease, and the development of antisense-based therapeutic approaches, and WP3 focuses on the dissection of ribosome biogenesis pathways to reveal disease-associated errors, and on ncRNA-mediated regulation of translation. The NCCR RNA & Disease will be jointly hosted by the University of Bern and the ETH Zürich, with additional participating teams located in Basel (FMI and Biozentrum) and Lausanne (EPFL).Added value for the Swiss scientific landscape and society: The NCCR RNA & Disease will provide a platform for high-quality, interdisciplinary education of students and postdocs in the rapidly growing field of RNA biology, thereby meeting the rising demand of the Swiss pharmaceutical and biotech industry for scientists with such specific knowledge. Our initiative will structure existing activities as well as initiate new collaborative projects among 16 academic labs of the consortium and beyond, with the long-term strategy to gradually develop the results of basic research towards medical and pharmaceutical applications. Moreover, the planned establishment of new assistant professorships and financial support for additional up to 6 junior groups will significantly enhance innovative RNA research in Switzerland and ensure its perennity. We expect that novel disease-related, therapeutically relevant RNA targets will be discovered, offering opportunities for industrial partners or for launching start-up companies. Simultaneously, the visibility of this important field at the frontier of modern life sciences will increase and help Switzerland to promote its reputation of a lighthouse for groundbreaking science.

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Modeling multi-layer large-scale data to decipher the translational regulatory code of cellular functions

Research Project  | 3 Project Members

The production of proteins from mRNAs (translation) is a central, most energy-consuming activity of cells. Yet most studies of gene expression regulation have focused on other steps of gene expression, particularly the synthesis of mRNAs based on the DNA template. Examples of translational control are known in the context of development or diseases such as cancers. However, it remains poorly understood how mutations in genes encoding translation factors lead to specific diseases or how translation is adjusted when cells respond to perturbations. In this project we will take a systematic approach to understand how translation is regulated in relation to the proliferation rate of cells. We will focus on the liver, a key metabolic organ that rapidly integrates a wide range of signals to synthesize many molecules of key relevance for the entire organism and that also retains the capacity for regeneration. With multi-layer omics data and mathematical models we will determine translation parameters of individual transcripts, identify regulatory elements and predict the impact of translation changes on the metabolic networks of cells. Through the analysis of human hepatocarcinoma samples, our study will elucidate the largely uncharted functional impact of translational control in a system that is highly relevant for human health, providing a blueprint for similar studies of other human cancers.

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System-level characterization of RNA-binding proteins that mediate the pathogenicity of human RNA viruses

Research Project  | 3 Project Members

Obwohl das Auftreten von antibiotikaresistenten Bakterien Anlass zu grosser Sorge gibt, hat die anhaltende Pandemie die Tatsache unterstrichen, dass Viren, insbesondere solche mit einem RNA-Genom, eine gleichwertige und allgegenwärtige Bedrohung für die menschliche Gesundheit und das Leben darstellen. Es wird auch häufig vermutet, dass chronische Virusinfektionen zu Krebs führen. Zum Beispiel wurde das Hepatitis-C-Virus mit Leberkrebs in Verbindung gebracht. Wie die Langzeitpersistenz des Virus im Wirt entsteht, ist daher eine Frage von grossem Interesse. Die Interaktion zwischen Viren und Wirtszellen ist äusserst komplex und es wurde viel Arbeit geleistet, um festzustellen, wie Viren verschiedene Komponenten von Wirtszellen ausbeuten, um ihre Replikation und / oder Persistenz zu fördern. Studien in den letzten Jahren haben gezeigt, dass viele Proteine RNA-Moleküle binden, sowie neue Wechselwirkungen zwischen RNA-bindenden Proteinen und Viren entdeckt. Was jedoch immer noch schlecht charakterisiert ist, ist die Bedeutung dieser Wechselwirkungen für die Wirtszellen. Beispielsweise könnte die Bindung eines Proteins an die Virus-RNA zu einer gestörten Lokalisierung des Proteins innerhalb der Zelle oder zum "Abfangen" des Proteins von Wirts-RNAs führen, was Konsequenzen für die Funktion der Wirtszelle hat. In diesem Projekt schlagen wir einen "System" -Ansatz vor, um zu bestimmen, wie sich das Netzwerk aus viraler RNA, und Proteinen und RNAs der Wirtszelle, während der frühen Infektionsphase mit zwei verschiedenen RNA-Viren ändert, dem Hepatitis C-Virus (HCV) einerseits und dem Coxsackie B3-Virus (CVB3) andererseits. Obwohl einige der mit dem Virus interagierenden Proteine bei beiden Viren dieselben sind, unterscheidet sich die Infektionsdynamik zwischen diesen beiden Viren, wobei HCV eine chronische Infektion verursacht, während CVB3 eine lytische Infektion verursacht. Durch die Gegenüberstellung dieser beiden Modellsysteme verbessern wir das derzeitige Verständnis, wie Wirtszellen umgebaut werden, um eine Umgebung bereitzustellen, in der das Virus fortbestehen kann. Da gezeigt wurde, dass RNA-bindende Proteine eine Schlüsselrolle bei Virusinfektionen spielen, wird unsere Studie neue Ansätze für die antivirale Therapie und zur Begrenzung der Langzeitpersistenz von Viren in Wirtszellen liefern.