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ERC Implementing Arrangements Call for Expression of Interest 2017 ERC Implementing Arrangements Call for Expression of Interest 2017 Project ID: Project Acronym: Evaluation Panel: 681178 G-EDIT LS1 Principal Investigator: Dr Mariusz Nowacki Host Institution: Universitat Bern - CH Mechanisms of RNA-guided genome editing in eukaryotes The goal of this project is to contribute to our understanding of RNA-mediated epigenetic mechanisms of genome regulation in eukaryotes. Ciliated protozoa offer a fantastic opportunity to investigate the complex process of trans-generational programming of chromosomal rearrangements, which is thought to serve as a form of immune defense against invasive DNA. Developmental processes in ciliates include extensive rearrangements of the germline DNA, including elimination of transposons and the precise excision of numerous single-copy elements derived from transposons. This process is considered to be maternally controlled because the maternal genome provides essential information in the form of RNA that determines the offspring's genome content and organization. This programmed DNA subtraction, the so-called ‘RNA scanning’ process, is mediated by trans-generational comparison between the germline and the maternal somatic genome. One of the most intriguing questions is how a complex population of small RNAs representing the entire germline genome can be compared to the entire rearranged maternal genome, resulting in the efficient selection of germline-specific RNAs, which are able to target DNA deletions in the developing genome. All this occurs in a very short time and involves a massively coordinated transport of all the components between three types of nuclei. This project focuses on characterizing the molecular machinery that can orchestrate the massive genome rearrangements in ciliates through nucleic acids and protein interactions. It also addresses the question how RNA targets DNA cleavage at the right place. In addition, this project aims to investigate the role of RNA in guiding chromosomal rearrangements in other eukaryotic systems, particularly in human cancer cells where genome editing often occurs on a large scale. This work may be the first step in providing novel insights into the process of programmed DNA rearrangements in higher eukaryotes. Keywords of the ERC project: Keywords that characterize the scientific profile of the potential visiting researcher/s: Index: -1 - Project ID: Project Acronym: Evaluation Panel: 640283 vidock LS1 Principal Investigator: Dr Matthieu Montes Host Institution: Conservatoire National Des Arts Et Metiers - FR 2D Conformal mapping of protein surfaces: applications to VIsualization and DOCKing software The goals of structural biology include developing a comprehensive understanding of the molecular shapes and forms embraced by biological macromolecules and extending this knowledge to understand how different molecular architectures are used to perform the chemical reactions that are central to life. Since the first resolution of protein structures by X-ray crystallography and NMR, structural biology seeks to provide this picture of biological phenomena at the molecular and atomic level by analyzing 3D structures. In the present proposal, we propose to change this paradigm by changing the mode of representation of protein surfaces to 2D maps. That will open new avenues for 1. the development of innovative high-throughput computation of protein interactions and relationships and 2. the emergence of new forms of visualization and analysis of protein structures and properties. We will apply this powerful tool of conformal mapping to structural biology by representing protein surfaces that are complex 3D surfaces in 2D conformal maps that we will call positive conformal maps. We will extend this representation by also generating the 2D conformal maps of the negatives of the 3D surface of the proteins. These positive and negative 2D conformal maps of the surface of proteins will constitute a new representation of the protein surfaces that will be the basis for innovative high-throughput and/or interactive simulation methods, visualization methods and more generally that will give an other insight on the structure of proteins. The major impact of this proposal lies in the fact that it will at last open the gates of the long awaited proteome docking. Using a simplified representation of protein surfaces will allow to perform faster complete cross docking calculations and create a new classification of the protein structures based on their surficial similarity. Keywords of the ERC project: protein interactions, shape similarity search, interactive simulation, data visualization Keywords that characterize the scientific profile of the potential visiting researcher/s: Index: -2 - Project ID: Project Acronym: Evaluation Panel: 648039 DUB-DECODE LS2 Principal Investigator: Dr Chunaram Choudhary Host Institution: Kobenhavns Universitet - DK Systematic Decoding of Deubiquitylase-Regulated Signaling Networks Cellular processes are largely governed by sophisticated protein posttranslational modification (PTM)- dependent signaling networks, and a systematic understanding of regulatory PTM-based networks is a key goal in modern biology. Ubiquitin is a small, evolutionarily conserved signaling protein that acts as a PTM after being covalently conjugated to other proteins. Reversible ubiquitylation forms the most versatile and largest eukaryote-exclusive signaling system, and regulates the stability and function of almost all proteins in cells. Deubiquitylases (DUBs) are ubiquitin-specific proteases that remove substrate-conjugated ubiquitin, and thereby regulate virtually all ubiquitylation-dependent signaling. Because of their central role in ubiquitin signaling, DUBs have essential functions in mammalian physiology and development, and the dysregulated expression and mutation of DUBs is frequently associated with human diseases. Despite their vital functions, very little is known about the proteins and ubiquitylation sites that are regulated by DUBs and this knowledge gap is hampering our understanding of the molecular mechanisms by which DUBs control diverse biological processes. Recently, we developed a mass spectrometry-based proteomics approach that allowed unbiased and site-specific quantification of ubiquitylation on a systems-wide scale. Here we propose to comprehensively investigate DUB-regulated ubiquitin signaling in human cells. We will integrate interdisciplinary approaches to develop next-generation cell models and innovative proteomic technologies to systematically decode DUB function in human cells. This will enable a novel and detailed understanding of DUB-regulated signaling networks, and open up new avenues for further research into the mechanisms and biological functions of ubiquitylation and of ubiquitin-like modifiers. Keywords of the ERC project: Cell Signaling, ubiquitination, mass spectrometry, proteomics Keywords that characterize the scientific profile of the potential visiting researcher/s: Cell Signaling, Chip-Seq, Molecular Biology, ubiquitination Index: -3 - Project ID: Project Acronym: Evaluation Panel: 716344 TREATCilia LS2 Principal Investigator: Dr Miriam Schmidts Host Institution: Stichting Katholieke Universiteit - NL Novel Therapeutic Avenues for dynein-related Ciliopathies Background: Cilia are hair-like, microtubule-based organelles protruding from most quiescent mammalian cells. They play essential roles in cell signalling (primary cilia) as well as movement of fluid (motile cilia). Although individually rare, cilia dysfunction affects up to 1 in 500 people in Europe, significantly reducing quality of life and lifespan due to dysfunction of multiple organs, including the kidneys, liver, heart, brain, retina, airways and the skeleton. To date, treatment is purely symptomatic. Aim and Approach: TREATCilia aims to decipher novel treatment avenues and improve clinical management for dynein-related ciliopathies. Next-generation sequencing based gene identification for dynein-related ciliopathies (ciliary chondrodysplasias and Primary Ciliary Dyskinesia, PCD) is employed to dissect the molecular basis and identify new therapeutic targets. Revealing genotype-phenotype mechanisms and their underlying cell signalling defects provides further insight into potential treatment options. Novel innovative curative approaches include high-throughput substance screening in model organisms such as the green algae Chlamydomonas and mammalian cells specially adapted for this purpose. Impact: Identification of novel ciliopathy genes will not only improve the biological understanding, but also reveal new treatment candidates. Furthermore, scrutinizing the molecular mechanisms of disease yields pharmacological entry points. TREATCilia develops a pre-clinical pipeline towards gene and mutation-specific treatments for hereditary conditions resulting from dynein-related ciliary dysfunction. Keywords of the ERC project: Cilia, dynein, zebrafish, CRISPR, whole exome sequencing, chondrodysplasia, situs inversus Keywords that characterize the scientific profile of the potential visiting researcher/s: Index: -4 - Project ID: Project Acronym: Evaluation Panel: 679146 EpigenomeProgramming LS2 Principal Investigator: Dr Christoph Bock Host Institution: Cemm - Forschungszentrum Fuer Molekulare Medizin Gmbh - AT An experimental and bioinformatic toolbox for functional epigenomics and its application to epigenetically making and breaking a cancer cell Epigenetic alterations can be detected in all cancers and in essentially every
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