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Index: - 1 -

ERC Visiting Fellowship Programmes

Call for Expression of Interest

2019

Index: - 1 -

Project ID:

Project Acronym:

Evaluation Panel:

681178 G-EDIT

LS1

Molecular and Structural

Biology and Biochemistry

Principal Investigator: Dr. MARIUSZ NOWACKI

Host Institution: Universitaet 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 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.

Project End Date: 30-APR-21

Index: - 2 -

Project ID:

Project Acronym:

Evaluation Panel:

693742 MERA

LS1

Molecular and Structural

Biology and Biochemistry

Principal Investigator: Dr. PETER HEGEMANN

Host Institution: Humboldt-Universitaet Zu Berlin, DE

Mechanism of Enzyme Rhodopsin Activation

Channelrhodopsin, which was discovered and described as a light-gated ion channel in my

laboratory, has revolutionized the field of neuroscience over the past decade by enabling researchers

to specifically activate selected neurons in a large ensemble of neuronal cells with short light flashes,

a technology we now call "Optogenetics." However, though highly desirable, the inactivation of

specific cells using moderate or low light intensities is not yet possible. The recently discovered rhodopsin-guanylyl-cyclase (RhGC) of the fungus Blastocladiella emersonii offers an elegant solution to this problem. Moreover, RhGC is a totally novel and uncharacterized sensory photoreceptor, and

the first member of an enzyme rhodopsin family that urgently awaits in-depth characterization.

Accordingly, the goal of the ͞mechanism of enzyme rhodopsin actiǀation" (MERA) proposal is to obtain a comprehensive understanding of this novel photoreceptor, and to determine its functionality for broad application in optogenetics and other research fields. The MERA project is

subdivided into four objectives. The first objective is the characterization and engineering of RhGC in

cell lines and neurons as well as coexpression of RhGC with a cGMP-gated K+ channel to develop a "Light-Hypopolarizer" for cell inactivation. The second objective is to understand the dynamics of RhGC using a variety of biophysical technologies including time resolved UV-vis, FTIR, and Raman and EPR spectroscopy. A third objective is the generation of crystals for X-ray crystallography and the development of a three dimensional RhGC model. The fourth and final objective is the computer- aided conversion of RhGC into a rhodopsin-phosphodiesterase (RhPDE) for down-regulation of the second messenger cGMP and/or cAMP using light. The ultimate outcome will be a detailed understanding of a novel class of sensory photoreceptors with new perspectives for broad optogenetic applications.

Project End Date: 30-SEP-21

Index: - 3 -

Project ID:

Project Acronym:

Evaluation Panel:

694694 ChromADICT

LS1

Molecular and Structural

Biology and Biochemistry

Principal Investigator: Dr. GENEVIEVE ALMOUZNI

Host Institution: Institut Curie, FR

Chromatin Adaptations through Interactions of Chaperones in Time A central question in chromatin biology is how to organize the genome and mark specific regions

with histone variants. Understanding how to establish and maintain, but also change chromatin

states is a fundamental challenge. Histone chaperones, escort factors that regulate the supply,

loading, and degradation of histone variants, are key in their placement at specific chromatin

landmarks and bridge organization from nucleosomes to higher order structures. A series of studies

have underlined chaperone-variant partner selectivity in multicellular organisms, yet recently,

dosage imbalances in natural and pathological contexts highlight plasticity in these interactions.

Considering known changes in histone dosage during development, one should evaluate chaperone

function not as fixed modules, but as a dynamic circuitry that adapts to cellular needs during the cell

cycle, replication and repair, differentiation, development and pathology. Here we propose to decipher the mechanisms enabling adaptability to natural and experimentally induced changes in the dosage of histone chaperones and variants over time. To follow new and old proteins, and control dosage, we will engineer cellular and animal models and exploit quantitative readout methods using mass spectrometry, imaging, and single-cell approaches. We will evaluate with an unprecedented level of detail the impact on i) soluble histone complexes and ii) specific chromatin landmarks (centromere, telomeres, heterochromatin and regulatory elements) and their

crosstalk. We will apply this to determine the impact of these parameters during distinct

developmental transitions, such as ES cell differentiation and T cell commitment in mice. We aim to define general principles for variants in nuclear organization and dynamic changes during

the cell cycle/repair and in differentiation and unravel locus specific-roles of chaperones as architects

and bricklayers of the genome, in designing and building specific nuclear domains.

Project End Date: 30-JUN-21

Index: - 4 -

Project ID:

Project Acronym:

Evaluation Panel:

694996 SIDSCA

LS1

Molecular and Structural

Biology and Biochemistry

Principal Investigator: Dr. KEITH CALDECOTT

Host Institution: University Of Sussex, UK

Defective DNA Damage Responses in Dominant Neurodegenerative Diseases DNA single-strand breaks (SSBs) are the most frequent DNA lesions arising in cells and are a major

threat to cell survival and genome integrity, as indicated by the elevated genetic deletion, embryonic

lethality, or neurological disease observed if single-strand break repair (SSBR) is attenuated. In

particular, SSBR defects are associated with hereditary neurodegeneration in humans, as illustrated

by the genetic diseases ataxia oculomotor apraxia-1 (AOA1), spinocerebellar ataxia with axonal

neuropathy-1 (SCAN1), and microcephaly with early onset seizures (MCSZ). However, two major questions remain: what are the mechanisms by which SSBs trigger neurodegeneration, and to what extent do SSBs contribute to other genetic and/or sporadic neurodegenerative disease? Based on exciting new data we now propose that the impact of SSBs on neurodegeneration extends beyond rare SSBR-defective diseases to include more common motor neurone diseases (amyotrophic lateral sclerosis) and the genetically dominant spinocerebellar ataxias (SCAs). Ultimately, we suggest that SSBs might also be an etiological factor in normal human ageing. Finally, again based on new data,

we propose that SSBs induce neurodegeneration by triggering over-activation of the SSB sensor

protein, PARP1; thereby identifying inhibitors of this protein (currently licensed for cancer treatment)

as a possible therapy for neurodegeneration. We will now address these hypotheses using a range of

cutting edge molecular/cellular techniques. In particular we will (a), systematically examine all

relevant amyotrophic lateral sclerosis/motor neurone disease (ALS/MND) and spinocerebellar ataxia (SCA) proteins for involvement in the DNA damage response, (b) Identify the mechanism/s by which ALS and SCA proteins engage in the DNA damage response, (c) Identify the role of ALS and SCA proteins in the DNA damage response, and (d) Explore PARP1 as a possible therapeutic target for treatment of neurodegenerative disease.

Project End Date: 30-SEP-21

Index: - 5 -

Project ID:

Project Acronym:

Evaluation Panel:

714102 CaBiS

LS1

Molecular and Structural

Biology and Biochemistry

Principal Investigator: Dr. GUSTAV BERGGREN

Host Institution: Uppsala Universitet, SE

Chemistry and Biology in Synergy -

Studies of hydrogenases using a combination of synthetic chemistry and biological tools My proposal aims to take advantage of my ground-breaking finding that it is possible to mature, or

activate, the [FeFe] hydrogenase enzyme (HydA) using synthetic mimics of its catalytic [2Fe] cofactor.

(Berggren et al, Nature, 2013) We will now explore the chemistry and (bio-)technological potential of

the enzyme using an interdisciplinary approach ranging from in vivo biochemical studies all the way to synthetic model chemistry. Hydrogenases catalyse the interconversion between protons and H2

with remarkable efficiency. Consequently, they are intensively studied as alternatives to Pt-catalysts

for these reactions, and are arguably of high (bio-) technological importance in the light of a future

͞hydrogen society".

The project inǀolǀes the preparation of noǀel ͞artificial" hydrogenases with the primary aim of

designing spectroscopic model systems via modification(s) of the organometallic [2Fe] subsite. In parallel we will prepare in vitro loaded forms of the maturase HydF and study its interaction with apo-HydA in order to further elucidate the maturation process of HydA. Moreover we will develop

the techniques necessary for in vivo application of the artificial activation concept, thereby paving

the way for a multitude of studies including the reactivity of artificial hydrogenases inside a living cell,

but also e.g. gain-of-function studies in combination with metabolomics and proteomics. Inspired by

our work on the artificial maturation system we will also draw from our knowledge of Nature's ΀FeS΁

cluster proteins in order to prepare a noǀel class of ͞miniaturized hydrogenases" combining synthetic

[4Fe4S] binding oligopeptides with [2Fe] cofactor model compounds.

Our interdisciplinary approach is particularly appealing as it not only provides further insight into

hydrogenase chemistry and the maturation of metalloproteins, but also involves the development of novel tools and concepts applicable to the wider field of bioinorganic chemistry.

Project End Date: 31-JAN-22

Index: - 6 -

Project ID:

Project Acronym:

Evaluation Panel:

715024 RAPID

LS1

Molecular and Structural

Biology and Biochemistry

Principal Investigator: Dr. SIMON ELSÄSSER

Host Institution: Karolinska Institutet, SE

Chromatin dynamics resolved by rapid protein labeling and bioorthogonal capture Histone proteins provide a dynamic packaging system for the eukaryotic genome. Chromatin integrates a multitude of signals to control gene expression, only some of which have the propensity to be maintained through replication and cell division. For our understanding of cellular memory and epigenetic inheritance we need to know what features characterize a stable, heritable chromatin state throughout the cell cycle. State-of-the-art methods such as ChIP-Seq provide population-based

snapshots of the epigenomic landscape but little information on the stability and relative importance

of each studied feature or modification. This project pioneers a rapid, sensitive and selective protein

labeling method (termed RAPID) for capturing genome-wide chromatin dynamics resolved over a period of time ranging from minutes to days. RAPID introduces a flexible time dimension in the form of pulse or pulse-chase experiments for studying genome-wide occupancy of a protein of interest by

next-gen sequencing. It can also be coupled to other readouts such as mass spectrometry or

microscopy. RAPID is uniquely suited for studying cell cycle-linked processes, by defining when and model system for pluripotency and lineage specification. RAPID will define fundamental rules for inheritance of histone and other chromatin-associated proteins and how they are modulated by the

fast cell cycle of pluripotent cells. Using RAPID in combination with other state-of-the art genetics

and epigenomics, I will collect multi-dimensional descriptions of the dynamic evolution and

propagation of functionally relevant chromatin states, such as interstitial heterochromatin and

developmentally regulated Polycomb domains.

Project End Date: 31-DEC-21

Index: - 7 -

Project ID:

Project Acronym:

Evaluation Panel:

724040 NascenTomiX

LS1

Molecular and Structural

Biology and Biochemistry

Principal Investigator: Dr. AXEL INNIS

Host Institution: Institut National De La Sante Et De La Recherche Medicale (Inserm), FR Ribosome inhibition by nascent or antimicrobial peptides

During the translation of genetic information into protein by the ribosome, nascent peptides

occasionally inhibit their own synthesis by interacting with the exit tunnel of the large ribosomal subunit. Known as nascent chain-mediated translational arrest, this process depends primarily upon the amino acid sequence of the arrest peptide. However, it can also rely upon the sensing of a low molecular weight ligand by the ribosome nascent chain complex, explaining its use for metabolite- dependent gene regulation in both bacteria and eukaryotes. Biochemical and structural studies of

arrest peptides have yielded key insights into their mode of action, but their ability to sense different

types of small molecules, their impact as regulators of gene expression in nature and the precise molecular details behind the arrest process are still largely unexplored. The groundbreaking aim of this ERC Consolidator research program is to decipher the arrest code governing nascent chain-mediated translational arrest in bacteria. My approach will be based on a technique recently developed in my group, referred to here as inverse toeprinting, which precisely maps the position of an arrested ribosome nascent chain complex on the mRNA while retaining the entire peptide-coding region up to the point of stalling. The overall aim will be achieved through four complementary objectives: (i) to assess the extent to which arrest peptides can act as small molecule sensors; (ii) to identify naturally occurring arrest

peptides in bacteria; (iii) to develop trans-inhibitory peptides that target the ribosome; and (iv) to

perform the structural characterization of new ribosome inhibitory peptides.

By addressing the natural diversity and molecular bases of the arrest process, this project will be the

key to understanding a unique form of gene regulation and a fundamental aspect of ribosome

function. It will also provide a handle for designing next-generation antibiotics.

Project End Date: 31-MAY-22

Index: - 8 -

Project ID:

Project Acronym:

Evaluation Panel:

759661 SPOCkS MS

LS1

Molecular and Structural

Biology and Biochemistry

Principal Investigator: Dr. CHARLOTTE UETRECHT

Host Institution: Heinrich-Pette Institut Leibniz Institut Fuer Experimentelle Virologie, DE Sampling Protein cOmplex Conformational Space with native top down Mass Spectrometry

local changes, such as processing of polyproteins, protein phosphorylation or conversion of

substrates. While labelling strategies combined with mass spectrometry (MS), such as hydrogen

deuterium exchange and hydroxyl footprinting, are very versatile in studying protein structure, these

remedy these by studying the footprinting and therefore exposed surface area on conformation and

mass selected species. Labelling still happens in solution avoiding gas phase associated artefacts. The

labelling positions are then read out using newly developed top-down MS technology. Ultra-violet and free-electron lasers will be employed to fragment the protein complexes in the gas phase. In

order to achieve the highest possible sequence and thus structural coverage, lasers will be

complemented by additional dissociation and separation stages to allow MSΔN. SPOCk'S MS will allow sampling conformational space of proteins and protein complexes and especially report about the transient nature of protein interfaces. Constraints derived in MS will be fed into a dedicated

software pipeline to deriǀe atomistic models. SPOCk'S MS will be used to study intracellular viral

protein complexes, especially coronaviral replication/transcription complexes, which are highly

flexible and often resist crystallisation and are barely accessible by conventional structural biology

techniques.

Objectives:

- Integrate labelling with complex species selective native MS for time-resolved structural studies - Combine fragmentation techniques to maximise information content from MS

- Develop software suite to analyse data and model protein complex structures based on MS

constraints - Apply SPOCk'S MS to protein compledžes of human pathogenic ǀiruses

Project End Date: 31-DEC-22

Index: - 9 -

Project ID:

Project Acronym:

Evaluation Panel:

787926 RIBOFOLD

LS1

Molecular and Structural

Biology and Biochemistry

Principal Investigator: Dr. MARINA RODNINA

Host Institution: Max Planck Gesellschaft Zur Foerderung Der Wissenschaften E.V., DE Ribosome Processivity and Co-translational Protein Folding

Protein domains start to fold co-translationally while they are being synthesized on the ribosome. Co-

translational folding starts in the confined space of the ribosomal polypeptide exit tunnel and is

modulated by the speed of translation. Although defects in protein folding cause many human

diseases, the mechanisms of co-translational folding and the link between the speed of translation and the quality of protein folding is poorly understood. Here I propose to study when, where and how proteins emerging from the ribosome start to fold, how the ribosome and auxiliary proteins bound at the polypeptide exit affect nascent peptide folding, what causes ribosome pausing during translation, and how pausing affects nascent peptide folding. Our recent results (Holtkamp et al.,

Science 2015; Buhr et al., Mol Cell 2016) provide the proof of principle for monitoring translation and

protein folding simultaneously at high temporal resolution. First, we will follow translation

processivity and folding trajectories for proteins of different domain structure types using time-

resolved ensemble kinetics and single-molecule setups. The structures of complexes with stalled folding intermediates will be solved by cryo-electron microscopy. Second, we will investigate the

effects of the chaperone trigger factor, the signal reCoGnition particle, and other protein biogenesis

factors on the folding landscape. Third, we will analyze transient ribosome pauses in vivo (based on ribosome profiling data) and in vitro (based on time-resolved translation assays and mathematical

modeling) and identify the events that cause pausing. Finally, we will probe how changes in

translational processivity affect the conformational landscape of a protein. We expect that these results will open new horizons in understanding co-translational protein folding and will help to understand the molecular basis of many diseases.

Project End Date: 31-JUL-23

Index: - 10 -

Project ID:

Project Acronym:

Evaluation Panel:

789121 EditMHC

LS1

Molecular and Structural

Biology and Biochemistry

Principal Investigator: Dr. ROBERT TAMPÉ

Host Institution: Johann Wolfgang Goethe Universitaet Frankfurt Am Main, DE How MHC-I editing complexes shape the hierarchical immune response Our body constantly encounters pathogens or malignant transformation. Consequently, the adaptive immune system is in place to eliminate infected or cancerous cells. Specific immune reactions are triggered by selected peptide epitopes presented on major histocompatibility complex class I (MHC-I) molecules, which are scanned by cytotoxic T lymphocytes. Intracellular transport, loading, and editing of antigenic peptides onto MHC-I are coordinated by a highly dynamic multisubunit peptide-loading complex (PLC) in the ER membrane. This multitasking machinery orchestrates the translocation of proteasomal degradation products into the ER as well as the loading and proofreading of MHC-I molecules. Sampling of myriads of different peptide/MHC-I allomorphs requires a precisely coordinated quality

control network in a single macromolecular assembly, including the transporter associated with

antigen processing TAP1/2, the MHC-I heterodimer, the oxidoreductase ERp57, and the ER chaperones tapasin and calreticulin. Proofreading by MHC-I editing complexes guarantees that only very stable peptide/MHC-I complexes are released to the cell surface. This proposal aims to gain a holistic understanding of the PLC and MHC-I proofreading complexes,

which are essential for cellular immunity. We strive to elucidate the mechanistic basis of the antigen

translocation complex TAP as well as the MHC-I chaperone complexes within the PLC. This high-

risk/high-gain project will define the inner working of the PLC, which constitutes the central

machinery of immune surveillance in health and diseases. The results will provide detailed insights

into the architecture and dynamics of the PLC and will ultimately pave the way for unraveling general

principles of intracellular membrane-embedded multiprotein assemblies in the human body.

Furthermore, we will deliver a detailed understanding of mechanisms at work in viral immune

evasion.

Project End Date: 31-DEC-23

Index: - 11 -

Project ID:

Project Acronym:

Evaluation Panel:

805230 Orgasome

LS1

Molecular and Structural

Biology and Biochemistry

Principal Investigator: Dr. ALEXEY AMUNTS

Host Institution: Stockholms Universitet, SE

Protein synthesis in organelles

Protein synthesis in mitochondria is essential for the bioenergetics, whereas its counterpart in

chloroplasts is responsible for the synthesis of the core proteins that ultimately converts sunlight into

the chemical energy that produces oxygen and organic matter. Recent insights into the mito- and chlororibosomes have provided the first glimpses into the distinct and specialized machineries that involved in synthesizing almost exclusively hydrophobic membrane proteins. Our findings showed: 1) mitoribosomes have different exit tunnels, intrinsic GTPase in the head of the small subunit, tRNA-

Val incorporated into the central protuberance; 2) chlororibosomes have divaricate tunnels; 3)

ribosomes from both organelles exhibit parallel evolution. This allows contemplation of questions regarding the next level of complexity: How these ribosomes work and evolve? How the ribosomal components imported from cytosol are assembled with the organellar rRNA into a functional unit being maturated in different compartments in organelles? Which trans-factors are involved in this

process? How the chlororibosomal activity is spatiotemporally coupled to the synthesis and

incorporation of functionally essential pigments? What are the specific regulatory mechanisms? To address these questions, there is a need to first to characterize the process of translation in

organelles on the structural level. To reveal molecular mechanisms of action, we will use antibiotics

and mutants for pausing in different stages. To reconstitute the assembly, we will systematically pull-

down pre-ribosomes and combine single particle with tomography to put the dynamic process in the context of the whole organelle. To understand co-translational operations, we will stall ribosomes and characterize their partner factors. To elucidate the evolution, we will analyze samples from different species.

Taken together, this will provide fundamental insights into the structural and functional dynamics of

organelles.

Project End Date: 30-APR-24

Index: - 12 -

Project ID:

Project Acronym:

Evaluation Panel:

819299 MIGHTY_RNA

LS1

Molecular and Structural

Biology and Biochemistry

Principal Investigator: Dr. CHIRLMIN JOO

Host Institution: Technische Universiteit Delft, NL Repurposing small RNA from ciliates for genome editing: single-molecule study

Genome editing is an essential tool for life sciences. Recent ground-breaking discovery in

microbiology drew our attention to the genome editing ability of bacteria (CRISPR). Since its

discovery, CRISPR has revolutionized the way of editing a genome. Despite its wide use, CRISPR-

genome editing has limitations, especially in the use for medical applications. Numerous studies have

shown that it suffers from the off-target effect. Its use is also restricted by its particular sequence

requirement and its poor accessibility to a structured genome. Furthermore, recent studies

suggested that it might act as a virulence factor within human cells. These limitations demand new genome editing tools. This proposal sets out to understand the molecular mechanism of Tetrahymena DNA elimination. This naturally occuring genome editing is mediated by a eukaryotic RNA system (Twi1). This system uses an entirely different mechanism from CRISPR and has potential to perform more effectively. I

will first investigate how small RNA-loaded Twi1 (͞target searcher") reCoGnizes its target and

whether its performance exceeds other target searchers including CRISPR/Cas9. I will use single-

molecule fluorescence for high resolution observations and develop a high-throughput single-

molecule method for transcriptome-wide understanding. Second, I aim to identify a Twi1-related DNA nuclease(s) that carries out DNA elimination. I will use cutting-edge tools of single-molecule pull-down and multi-color FRET together with mass spectrometry. The nanoscopic understanding of

a searcher (Twi1) and the identification of a nuclease will help create a new genome editing tool (e.g.

a fusion of Twi1 and the nuclease) that potentially perform better than Cas9. Thereby, this

fundamental study on ͞mighty RNA" will make a long-term impact for applications in science and technology. To realize this ambitious project, I will utilize my experience of studying small RNAs (funded by ERC Starting Grant).

Project End Date: 30-APR-24

Index: - 13 -

Project ID:

Project Acronym:

Evaluation Panel:

677748 Ubl-Code

LS2

Genetics, Genomics,

Bioinformatics and

Systems Biology

Principal Investigator: Dr. YIFAT MERBL

Host Institution: Weizmann Institute Of Science, IL Revealing the ubiquitin and ubiquitin-like modification landscape in health and disease Post-translational modifications (PTMs) of proteins are a major tool that the cell uses to monitor events and initiate appropriate responses. While a protein is defined by its backbone of amino acid

sequence, its function is often determined by PTMs, which specify stability, activity, or cellular

localization. Among PTMs, ubiquitin and ubiquitin-like (Ubl) modifications were shown to regulate a variety of fundamental cellular processes such as cell division and differentiation. Aberrations in these pathways have been implicated in the pathogenesis of cancer. Over the past decade high- throughput genomic and transcriptional analyses have profoundly broadened our understanding of the processes underlying cancer development and progression. Yet, proteomic analyses and the PTM landscape in cancer, remained relatively unexplored. Our goal is to decipher molecular mechanisms of Ubl regulation in cancer. We will utilize the PTM profiling technology that I developed and further develop it to allow for subsequent MS analysis. Together with cutting-edge genomic, imaging and proteomic technologies, we will analyze novel

aspects of PTM regulation at the level of the enzymatic machinery, the substrates and the

downstream cellular network. We will rely on ample in-vitro and in-vivo characterization of Ubl

conjugation to:a. Elucidate the regulatory principles of substrate specificity and reCoGnition. b.

Understand signalling dynamics in the ubiquitin system. c. Reveal how aberrations in these pathways may lead to diseases such as cancer. Identifying both the Ubl modifying enzymes and the modified substrates will form the basis for deciphering the molecular pathways in which they operate in the cell and the principles of their dynamic regulation. Revealing the PTM regulatory code presents a unique opportunity for the development of novel therapeutics. More broadly, our approaches may provide a new paradigm for addressing other complex biological questions involving PTM regulation.

Project End Date: 30-APR-21

Index: - 14 -

Project ID:

Project Acronym:

Evaluation Panel:

694282 LYSOSOMICS

LS2

Genetics, Genomics,

Bioinformatics and

Systems Biology

Principal Investigator: Dr. ANDREA BALLABIO

Host Institution: Fondazione Telethon, IT

Functional Genomics of the Lysosome

For a long time the lysosome has been ǀiewed as a ͞static" organelle that performs ͞routine" work

for the cell, mostly pertaining to degradation and recycling of cellular waste. My group has

challenged this view and used a systems biology approach to discover that the lysosome is subject to

a global transcriptional regulation, is able to adapt to environmental clues, and acts as a signalling

hub to regulate cell homeostasis. Furthermore, an emerging role of the lysosome has been identified

in many types of diseases, including the common neurodegenerative disorders Parkinson's and

Alzheimer's. These findings haǀe opened entirely new fields of inǀestigation on lysosomal biology,

suggesting that there is a lot to be learned on the role of the lysosome in health and disease. The goal of LYSOSOMICS is to use ͞omics" approaches to study lysosomal function and its regulation in

normal and pathological conditions. In this ͞organellar systems biology project" we plan to perform

several types of genetic perturbations in three widely used cell lines and study their effects on

lysosomal function using a set of newly developed cellular phenotypic assays. Moreover, we plan to identify lysosomal protein-protein interactions using a novel High Content FRET-based approach. Finally, we will use the CRISPR-Cas9 technology to generate a collection of cellular models for all lysosomal storage diseases, a group of severe inherited diseases often associated with early onset neurodegeneration. State-of-the-art computational approaches will be used to predict gene function and identify disease mechanisms potentially exploitable for therapeutic purposes. The physiological relevance of newly identified pathways will be validated by in vivo studies performed on selected genes by using medaka and mice as model systems. This study will allow us to gain a comprehensive understanding of lysosomal function and dysfunction and to use this knowledge to develop new therapeutic strategies.

Project End Date: 30-SEP-21

Index: - 15 -

Project ID:

Project Acronym:

Evaluation Panel:

716024 GLYCONOISE

LS2

Genetics, Genomics,

Bioinformatics and

Systems Biology

Principal Investigator: Dr. CHRISTOPH RADEMACHER

Host Institution: Max Planck Gesellschaft Zur Foerderung Der Wissenschaften E.V., DE Emergent properties of cell surface glycosylation in cell-cell communication

The surface of every living cell is covered with a dense matrix of glycans. Its particular composition

and structure codes important messages in cell-cell communication, influencing development, differentiation, and immunological processes. The matrix is formed by highly complex biopolymers

whose compositions vary from cell to cell, even between genetically identical cells. This gives rise to

population noise in cell-cell communication. A second level of noise stems from glycans present on

the same cell that disturb the decoding of the message by glycans binding receptors through

competitive binding. Glycan-based communication is characterized by a high redundancy of both glycans and their receptors. Thus, noise and redundancy emerge as key properties of glycan-based cell-cell communication, but their extent and function are poorly understood. By adapting a transmitter-receiver model from communication sciences and combining it with state- of-the-art experimental techniques from biophysics and cell biology, we will address two fundamental questions: What is the role of the redundancy in glycan-based communication? Howquotesdbs_dbs19.pdfusesText_25

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