ERC FUNDED PROJECTS

Currently, more than 30% of all Europeans suffer from one or more allergic disorder but treatment is still mostly symptomatic due to a lack of understanding the underlying causality. Allergies are caused by type 2 immune responses triggered by recognition of harmless antigens. Both genetic and environmental factors have been proposed to favour allergic predisposition and both factors have a huge impact on the symbiotic microbiota and the intestinal immune system. Recently we and others showed that the transcription factor ROR(γt) seems to play a key role in mucosal tolerance in the gut and also regulates intestinal type 2 immune responses. Based on these results I postulate two major events in the gut for the development of an allergy in the lifetime of an individual: First, a failure to establish mucosal tolerance or anergy constitutes a necessity for the outbreak of allergic symptoms and allergic disease. Second, a certain ‘core’ microbiome or pathway of the intestinal microbiota predispose certain individuals for the later development of allergic disorders. Therefore, I will address the following aims: 1) Influence of ROR(γt) on mucosal tolerance induction and allergic disorders 2) Elucidate the T cell receptor repertoire of intestinal Th2 and ROR(γt)+ Tregs and assess the role of alternative NFκB pathway for induction of mucosal tolerance 3) Identification of ‘core’ microbiome signatures or metabolic pathways that favour allergic predisposition ALLERGUT will provide ground-breaking knowledge on molecular mechanisms of the failure of mucosal tolerance in the gut and will prove if the resident ROR(γt)+ T(reg) cells can function as a mechanistic starting point for molecular intervention strategies on the background of the hygiene hypothesis. The vision of ALLERGUT is to diagnose mucosal disbalance, prevent and treat allergic disorders even before outbreak and thereby promote Public Health initiative for better living.

1 498 175 €

Start date: 2017-07-01, End date: 2022-06-30

Embedded Control software plays a critical role in many safety-critical applications. For instance, modern vehicles use interacting software and hardware components to control steering and braking. Control software forms the main core of autonomous transportation, power networks, and aerospace. These applications are examples of cyber-physical systems (CPS), where distributed software systems interact tightly with spatially distributed physical systems with complex dynamics. CPS are becoming ubiquitous due to rapid advances in computation, communication, and memory. However, the development of core control software running in these systems is still ad hoc and error-prone and much of the engineering costs today go into ensuring that control software works correctly. In order to reduce the design costs and guaranteeing its correctness, I aim to develop an innovative design process, in which the embedded control software is synthesized from high-level correctness requirements in a push-button and formal manner. Requirements for modern CPS applications go beyond conventional properties in control theory (e.g. stability) and in computer science (e.g. protocol design). Here, I propose a compositional methodology for automated synthesis of control software by combining compositional techniques from computer science (e.g. assume-guarantee rules) with those from control theory (e.g. small-gain theorems). I will leverage decomposition and abstraction as two key tools to tackle the design complexity, by either breaking the design object into semi-independent parts or by aggregating components and eliminating unnecessary details. My project is high-risk because it requires a fundamental re-thinking of design techniques till now studied in separate disciplines. It is high-gain because a successful method for automated synthesis of control software will make it finally possible to develop complex yet reliable CPS applications while considerably reducing the engineering cost.

1 470 800 €

Start date: 2019-02-01, End date: 2024-01-31

Leukocytes are the key components of the immune system that fight infections and provide tissue repair, yet their migration patterns throughout the body over the course of a day are completely unknown. Circadian, ~24 hour rhythms are emerging as important novel regulators of immune cell migration and function, which impacts inflammatory diseases such as myocardial infarction and sepsis. Altering leukocyte tissue infiltration and activation at the proper times provides an option for therapy that would maximize the clinical impact of drugs and vaccinations and minimize side effects. We aim to create a four-dimensional map of leukocyte migration to organs in time and space and investigate with epigenetics techniques the molecular mechanisms that regulate cell-type specific rhythms. We will functionally define the daily oscillating molecular signature(s) of leukocytes and endothelial cells with novel proteomics approaches and thus identify a circadian traffic code that dictates the rhythmic migration of leukocyte subsets to specific organs under steady-state and inflammatory conditions with pharmacological and genetic tools. We will assess the impact of lineage-specific arrhythmicities on immune homeostasis and leukocyte trafficking using an innovative combination of novel genetic tools. Based on these data we will create a model predicting circadian leukocyte migration to tissues. The project combines the disciplines of immunology and chronobiology by obtaining unprecedented information in time and space of circadian leukocyte trafficking and investigating how immune-cell specific oscillations are generated at the molecular level, which is of broad impact for both fields. Our extensive experience in the rhythmic control of the immune system makes us well poised to characterize the molecular components that orchestrate circadian leukocyte distribution across the body.

1 497 688 €

Start date: 2015-09-01, End date: 2020-08-31

"CON-HUMO focuses on novel concepts for automatic control based on data-driven human models and machine learning. This enables innovative control applications that are difficult if not impossible to realize using traditional control and identification methods, in particular in the challenging area of smart human-machine interaction. In order to achieve intuitive and efficient goal-oriented interaction, anticipation is key. For control selection based on prediction a dynamic model of the human interaction behavior is required, which, however, is difficult to obtain from first principles. In order to cope with the high complexity of human behavior with unknown inputs and only sparsely available training data we propose to use machine-learning techniques for statistical modeling of the dynamics. In this new field of human interaction modeling – data-driven and machine-learned – control methods with guaranteed properties do not exist. CON-HUMO addresses this niche. Key methodological innovation and breakthrough is the merger of probabilistic learning with model-based control concepts through model confidence and prediction uncertainty. For the sake of concreteness and evaluation the focus is on one of the most challenging problem classes, namely physical human-machine interaction: Because of the physical contact between the human and the machine not only information, but also energy is exchanged posing fundamental challenges for real-time human-adaptive and safe decision making/control and requiring provable stability and performance guarantees. The developed methods are a direct enabler for societally important applications such as machine-based physical rehabilitation, mobility and manipulation aids for elderly, and collaborative human-machine production systems. With its fundamental results CON-HUMO lays the ground for the systematic control design for smart human-machine/infrastructure interaction."

1 494 640 €

Start date: 2014-02-01, End date: 2019-01-31

Macrophage differentiation programs are critical for the outcome of immunity against infection, chronic inflammatory diseases and cancer. How diverse inflammatory signals are translated to macrophage programs in the large range of human pathologies is largely unexplored. In the last years we focused on macrophage differentiation in granulomatous diseases. These affect millions worldwide, including young adults and children and tend to run a chronic course, with a high socioeconomic burden. Their common hallmark is the formation of granulomas, macrophage-driven structures of organized inflammation that replace healthy tissue. We revealed that macrophage precursors in granulomas experience a replication block and trigger the DNA Damage Response (DDR), a fundamental cellular process activated in response to genotoxic stress. This leads to the formation of multinucleated macrophages with tissue-remodelling signatures (Herrtwich, Cell 2016). Our work unravelled an intriguing link between genotoxic stress and granuloma-specific macrophage programs. The molecular pathways regulating DDR-driven macrophage differentiation and their role in chronic inflammatory pathologies remain however a black box. We hypothesize that the DDR promotes macrophage reprogramming to inflammation-maintaining modules. Such programs operate in granulomatous diseases and in chronic arthritis. Using state-of-the art genetic models, human tissues and an array of techniques crossing the fields of immunology, cell biology and cancer biology, our goal is to unravel the macrophage-specific response to genotoxic stress as an essential regulator of chronic inflammation-induced pathologies. The anticipated results will provide the scientific community with new knowledge on the role of genotoxic stress in immune dysregulation and will carry tremendous implications for the therapeutic targeting of macrophages in the context of chronic inflammatory diseases and cancer.

1 500 000 €

Start date: 2019-04-01, End date: 2024-03-31

"The incidence of chronic immune-mediated inflammatory diseases is continually increasing. Chronic inflammation has been linked to intestinal carcinogenesis, which is the second leading cause of cancer-related deaths. The cause of this increase could be the unprecedented dietary abundance typical of “Western” countries. Different types of diets shape the genetic composition and metabolic activity of human intestinal microorganisms; microbiota. There is a continuous cross talk between the microbiota and the immune system. For these reasons, the hypothesis that a “bad” diet promotes a chronic state of intestinal inflammation by shaping the microbiota and in turn carcinogenesis could be supported. However, this hypothesis and whether this is a reversible process remain to be tested. It has recently been shown that the composition and metabolism of the microbiota is plastic and it can be rapidly “reprogrammed” by switching to a healthier diet. This plastic behaviour has also been attributed to T helper cells. We have shown that Th17 cells, originally thought to be a stable T helper linage, can convert into a more pathogenic phenotype contributing to chronic inflammation or can acquire regulatory functions promoting the resolution of the inflammation. This project aims to reveal whether mouse and human Th17 cells can quickly adapt to the microbiota as the microbiota does to the diet and in turn mediate the diet effects. By using a unique set of sophisticated transgenic mice we will also test whether the immune system can be corrected by a “simple” change in diet – a widely held belief not yet substantiated. Studying the potential ""synchronized ballet"" of the diet and the immune system will reveal both the enormous dynamism and the revolutionary therapeutic opportunities intrinsic to T cell biology. This project will furthermore identify molecular targets for pharmacological treatments to reverse inflammatory diseases when a simple diet change no longer suffices."

1 499 695 €

Start date: 2016-12-01, End date: 2021-11-30

The rapid growth of data traffic requires radically new approaches for high-speed data transmission to increase the bandwidth and power efficiency by orders of magnitude. The proposed research aims at novel system and device concepts for low-energy high-capacity optical interconnects in data centers. Data rates of 10 Tbit/s and beyond are envisaged by coherent multicarrier transmission. Parametric frequency conversion in high-Q Kerr-nonlinear resonators will be used to generate broadband combs of frequency-locked optical carriers. Integrated silicon photonic systems will allow for power-efficient multichannel modulation and detection. Novel reconfigurable optical signal processors will avoid excessive digital post-processing and hence reduce overall energy consumption.

1 498 800 €

Start date: 2012-01-01, End date: 2016-12-31

"Adoptive T cell therapy is a promising approach in various clinical settings, from target-specific immune reconstitution fighting cancer and chronic infections to combating undesired immune reactivity during auto-immunity and after organ transplantation. However, its clinical application is currently hampered by: 1) the acquisition of senescence during the required in vitro expansion phase of T cells which limits their survival and fitness after infusion into the patient, and 2) the functional plasticity of T cells, which is sensitive to the inflammatory environment they encounter after transfusion and which might result in a functional switch from the desired effect (e.g. immunosuppressive) to the opposite one (pro-inflammatory). I want to tackle these obstacles from a new molecular angle, utilizing the profound impact of epigenetic mechanisms on the senescence process as well as on the functional imprinting of T lymphocytes. Epigenetic players such as DNA methylation essentially contribute to T cell differentiation and harbor the unique prospect to imprint a stable developmental and functional state in the genomic structure of a cell, as we could recently show in our basic immune-epigenetic studies. Therefore, I here propose to equip T lymphocytes with the required properties for their successful and safe therapeutic application, including their functional fine-tuning according to the clinical need by directed modifications of the epigenome ('Epi-tuning'). To reach these goals I want: 1) to reveal strategies for the directed manipulation of the epigenetically-driven mechanism of cellular senescence and 2) to apply state-of-the-art CRISPR/Cas9-mediated epigenetic editing approaches for the imprinting of a desired functional state of therapeutic T cell products. These innovative epigenetic ""one-shot"" manipulations during the in vitro expansion phase should advance T cell therapy towards improved efficiency, stability as well as safety."

1 489 725 €

Start date: 2019-01-01, End date: 2023-12-31

"Inflammasomes are intracellular danger-sensing protein complexes that are important for host protection. They initiate inflammation by controlling the activity of the proinflammatory cytokine interleukin-1β (IL-1β). Unlike most other cytokines, IL-1β is produced and retained in the cytoplasm in an inactive pro-form. Inflammasome-dependent maturation of proIL-1β is mediated by the common component of all inflammasomes, the protease caspase-1. Caspase-1 also controls the secretion of IL-1β, but the mechanism and route of secretion are unknown. We have recently demonstrated that the ability of caspase-1 to control IL-1β secretion is not dependent on its protease activity, but rather on a scaffold or adapter function of caspase-1. Furthermore, we and others could show that caspase-1 can control the secretion of non-substrates like IL-1α. These insights provide us with new and potentially revealing means to investigate the downstream effector functions of caspase-1, including the route and mechanism of IL-1 secretion. We will develop new tools to study the process of IL-1 secretion by microscopy and the novel mode-of-action of caspase-1 through the generation of transgenic models. Despite the important role of IL-1 in host defence against infection, dysregulated inflammasome activation and IL-1 production has a causal role in a number of acquired and hereditary auto-inflammatory conditions. These include particle-induced sterile inflammation (as is seen in gout and asbestosis), hereditary periodic fever syndromes, and metabolic diseases like diabetes and atherosclerosis. Currently, recombinant proteins that block the IL-1 receptor or deplete secreted IL-1 are used to treat IL-1-dependent diseases. These are costly treatments, and are also therapeutically cumbersome since they are not orally available. We hope that a better understanding of caspase-1-mediated secretion of IL-1 will unveil mechanisms that may serve as targets for future therapies for these diseases."

1 495 533 €

Start date: 2014-03-01, End date: 2019-02-28

Multiple Sclerosis (MS), an autoimmune demyelinating disease affecting the central nervous system (CNS), causes tremendous disability in young adults and inflicts huge economic burden on the society. The incidence of MS is steadily increasing in many countries arguing for environmental factors driven changes in disease induction. How and which environmental factors contribute to disease initiation and progression is unknown. Using a spontaneous mouse model of MS, we have shown that the gut microbiota is essential in triggering CNS autoimmunity. In contrast to the mice housed in conventional housing conditions, germ free (GF) mice, devoid of gut bacteria, were protected from spontaneous experimental autoimmune encephalomyelitis (sEAE). Re-colonization of GF mice with a complex regular gut flora derived from specific pathogen free (SPF) mice resulted in sEAE within 2-3 months. The re-colonization also triggered pro-inflammatory T and B cell responses. However, colonization of GF mice with a reduced gut flora failed to induce sEAE during our observation period suggesting a “specific” rather than a “broader” microbial trigger. In this proposal, I want to study the role of gut microbiota in CNS autoimmunity with the following aims: Aim 1: CNS autoimmunity triggering/protecting gut microbes and host immune responses I want to study how and which gut bacterial species are modulating CNS autoimmunity to better understand the origin of autoimmune responses and their relation to host immune responses. Aim 2: Molecular mechanisms of sensing of gut microbiota and microbial metabolites during CNS autoimmunity I want to identify the molecular pathways that are involved in sensing the gut microbiota and its metabolites which are relevant to CNS autoimmunity. Aim 3: Therapeutic application of gut microbiota for CNS autoimmunity I want to identify therapeutic strategies targeting gut microbiota to limit the development of inflammatory processes during CNS autoimmunity.

1 499 946 €

Start date: 2015-06-01, End date: 2020-05-31

Antibodies are destined to neutralize pathogens and can prevent and fight infectious diseases. Over the last years, advances in single B cell cloning resulted in the isolation of highly potent and broad HIV-1 neutralizing antibodies (bNAbs) that have been shown to prevent SHIV infection in non-human primates (NHPs). Recently, we have demonstrated that a combination of bNAbs can suppress HIV-1 replication in humanized mice, reducing viremia to undetectable levels. Moreover, bNAb therapy of SHIV-infected NHPs induced a rapid decline in viremia, followed by a prolonged control due to the long half-life of the antibodies. While these results strongly encourage the clinical evaluation of bNAbs in HIV-1 therapy, it is of critical importance to understand how the therapeutic potential of antibodies can be harnessed in the most effective way. Therefore, we aim to: I.) Identify exceptionally potent HIV-1 neutralizing antibodies that will be a crucial component of immunotherapy. By establishing novel methods for single-cell sorting and high-throughput sequencing we want to identify bNAbs targeting novel epitopes. II.) Prevent HIV-1 escape applying rationally designed treatment strategies targeting conserved functional sites for HIV-1 entry. III.) Evaluate immune markers and function in relation to bNAb administration in humans. Being at the forefront of one of the first clinical trials studying an HIV-1-directed bNAb, we will have the unique opportunity to investigate the interplay of antibody therapy and the host immune system. This proposal aims to strongly advance the field of HIV-1 antibody therapy and therefore enable the introduction of a new therapeutic modality for HIV-1, and will gain insights for antibody-mediated therapy in other infectious diseases.

1 500 000 €

Start date: 2016-01-01, End date: 2020-12-31

Humans have two ears – and for good reason: So-called binaural hearing is critical not only for localizing acoustic events but also for selectively focusing on a target sound while suppressing sound from other directions. In order to perform these tasks, neural circuits with the most temporally precise processing within the entire nervous system have evolved. 360 million people have impaired hearing. Although hearing aids and cochlear implants help restore audibility, they provide insufficient benefit in restoring the advantages of true binaural hearing. IBiDT is designed to fundamentally change this perspective. Appreciating the individual nature of each hearing deficit, it will provide the means of diagnosing pathologies, not just the perceptual symptoms. IBiDT will suggest algorithms specific to the individual detailed patient profile and suggest therapeutic interventions specific to the listening situation. To achieve these aims, a multidisciplinary approach in which both auditory and non-auditory aspects of patient profiles and a computer model simulating the impaired auditory system will, together, transform diagnosis of hearing impairment from one concerned with audibility to one concerned with effective communication in any listening environment. Binaural hearing is an ideal conceptual framework in which to investigate this approach as it increases greatly the number of possible pathologies, compared to unilateral diagnostics. The binaural hearing system is also ideal to investigate because it allows for large improvements in listening performance. Despite significant R&D expenditure, cochlear-implant performance has plateaued over the last 15 years, at least with respect to unilateral devices. Improvements from Individualized Binaural Diagnosis and Technology will have a large, positive impact on the increasing number of bilateral cochlear implant users (many of them children), as well as on the many tens of millions of people who use hearing aids.

1 500 000 €

Start date: 2018-01-01, End date: 2022-12-31

Pathogen proliferation has profound implications for its persistence, treatment strategies, and the induction and execution of protective immune responses. In vivo, pathogen proliferation rates are heterogenic, confronting the immune system with a variety of microbial physiological states. It is unknown if, and by what molecular mechanism, the immune response can distinguish these different states on a cellular level. Also, understanding the link between pathogen proliferation and immune cell dynamics could provide critical information on how infections can be controlled, and how to counteract pathogen persistence and antibiotic resistance. However, this question has never been addressed due to difficulties in studying the dynamics of immune cells and at the same time probing pathogen proliferation. In this project, we will make use of a novel in vivo reporter system that I have developed, in order to determine the role of the pathogen's proliferation for its interaction with the immune system. Specifically, we will (1) determine the tissue niche in which the pathogen proliferates, (2) investigate the differential dynamics of phagocyte-pathogen- and of T cell-APC-interactions related to pathogen proliferation rate, (3) manipulate the relationship between pathogen proliferation and immune cell dynamics by using proliferation-deficient mutants and optogenetic pathogen inactivation, (4) identify signaling pathways that are differentially induced in cells infected by high versus low proliferating pathogens, and test their involvement in differential immune cell dynamics related to pathogen proliferation. ImmProDynamics will for the first time provide insights into how cells of the immune system react to distinct pathogen proliferative states in vivo. This will greatly expand our knowledge of host-pathogen interactions, which will be critical for the design of efficient vaccines and antimicrobial therapy.

1 499 525 €

Start date: 2017-03-01, End date: 2022-02-28

Communication and data storage systems are indispensable parts of our every-day life. However, these systems deal with severe challenges in security and reliability. Security is important whenever a user communicates or stores sensitive data, e.g., medical information; reliability has to be guaranteed to be able to transmit or store information while noise occurs. Algebraic codes (ACs) are a powerful means to achieve both. Within inCREASE, I will construct and evaluate special codes for security applications and DNA storage. The tasks are structured into three work packages: (1) post-quantum secure code-based cryptosystems, (2) secure key regeneration based on ACs, (3) ACs for DNA-based storage systems. The focus of inCREASE lies on innovative theoretical concepts. The goal of work package (1) is to investigate and design code-based cryptosystems; one promising idea is to apply insertion/deletion correcting codes. The security of these systems will be analysed from two points of view: structural attacks on the algorithms and hardware implementations with side-channel attacks. Secure cryptographic key regeneration is the goal of (2) and can be achieved by physical unclonable functions (PUFs). Here, ACs are necessary to reproduce the key reliably. This project will study the error patterns that occur in PUFs, model them theoretically, and design suitable coding schemes. The investigation on (3) will start with a study of the data of existing DNA storage systems. The outcome will be an error model that will include insertions, deletions, substitutions, and duplications. Therefore, inCREASE will design ACs for these error types. This will be especially challenging regarding the mathematical concepts. These codes will be evaluated by simulations and using data sets of DNA storage systems. This project is high risk/high gain with impact not only to storage and security, but to the methodology as well as other areas such as communications.

1 471 750 €

Start date: 2019-03-01, End date: 2024-02-29

Bioelectronic medicine may soon replace systemic drugs for treating some chronic conditions. The clinician will implant a miniature laboratory to deliver and coordinate a multi-modal treatment program directly at the affected tissue. The technology to bring this vision to the clinic is not yet available. The IntegraBrain project will contribute by building an implantable network of sensors and actuators. Actuators will deploy electricity, light, drugs and thermal energy as modalities of the therapeutic program, while sensors will monitor its progress. A key technological advance will be a method for direct writing of the sensor-actuator network. To achieve this, we will develop a palette of functional inks where each ink supports one of the therapeutic modalities. The technology has the potential to be tailored for applications in soft tissue organs, especially in the nervous system, where injury or degeneration can result in chronic disability. We will apply IntegraBrain technology in two niches of the nervous system in rodents. In the central nervous system, we will demonstrate seizure control by multi-modal neuromodulation. In the peripheral nervous system, we will demonstrate reversible block and excitation. For the first time, we will observe if multi-modal neuromodulation leads to synergistic effects on the nervous system. With the IntegraBrain project, we hope to catalyse pre-clinical development of implantable human-machine interfaces for therapeutic applications.

1 496 000 €

Start date: 2019-01-01, End date: 2023-12-31

Pathogens exploit cellular resources for their own benefit and their propagation. Co-evolution of viruses and their hosts led to the establishment of very specific interactions between both partners. The balance between both, the viral attack and the cellular defense mechanisms, dictates the outcome of an infection, either leading to a cure, to disease or life-long co-existence. Efforts from many laboratories have focused on virus-host interactions, mostly by testing isolated protein-protein interactions or by employing transcriptome analysis. Although this undoubtedly has been highly valuable to our knowledge on virus-host interactions, it is also clear that most virus-host interactions do not occur on transcriptome level and neither involve single protein-protein interactions. Here I propose to systematically test the impact of virus infection on the host proteome (iViP) by using the newest generation of mass spectrometry-based discovery tools combined with infection biology. iViP divides in three interconnected parts that individually and collectively warrant success: Part I evaluates changes in the abundance of the proteins after virus infection and correlates this to mRNA levels, determined by RNA sequencing. Part II identifies proteome-wide post-translational modifications that would be indicative for an involvement in infection biology. Part III dissects the role of virus stimulated/altered proteins in the antiviral protein-protein interaction network. Lastly, identified proteins will be validated in a two –step procedure involving a large-scale validation strategy and further focusing on few selected interactors. A comprehensive coherent data set describing and functionally explaining the cellular changes after encounter of a variety of viral pathogens on a proteome level would complement or even succeed currently available data sets and become invaluable to basic and translational research of the future.

1 498 896 €

Start date: 2012-11-01, End date: 2017-10-31

The aim of this proposal is to examine the role of inflammatory signalling pathways in murine models of liver and biliary disease by application of conditional gene targeting using cre/loxP technology. Previous studies have provided evidence that the NF-kB pathway and its activating kinase complex – consisting of three subunits: IKK1, IKK2 and NEMO – are crucial regulators of liver physiology and pathology, but their differential, cell specific functions in the liver are currently only poorly understood. The first part of this proposal will focus on the evaluation of molecular mechanisms underlying the development of hepatocellular carcinoma in a setting of chronic hepatitis. By using a novel mouse model of spontaneous liver cancer based on conditional deletion of NEMO in hepatocytes, the functions of cytokines, specific intracellular signalling pathways, the innate and adaptive immune system and the role of hepatic stem cells in hepatitis and carcinogenesis will be examined. In the second part of this proposal, we will extend these studies by evaluating the function of NEMO/NF-kB in other hepatic cell compartments, specifically the function of NEMO in hepatic stellate cells and liver fibrosis, the endothelial function of NEMO/NF-kB in an in vivo model of hepatic ischemia-reperfusion injury and the role of the NF-kB pathway in biliary epithelial cells and inflammatory biliary diseases. Finally, in the third part of this proposal we will analyse the unknown intrahepatic role of non-canonical, IKK1-dependent signalling pathways and the function of TAK1 – a molecule at the interface between inflammatory and developmental pathways – in liver injury, fatty-liver-disease and insulin-resistance. Knowledge gained by these studies and the further understanding of the cell specific hepatic function of NF-kB and related pathways might build the basis for the development of novel pharmacological approaches for the future treatment of liver diseases and cancer in humans.

1 600 356 €

Start date: 2008-09-01, End date: 2014-08-31

Plasmodium sporozoites are the motile forms of the malaria parasite injected into the host by a mosquito. Sporozoite motility is essential for tissue penetration as well as host cell invasion and thus pathogenesis suggesting that blocking motility could potentially add a new way in controlling malaria. It is dependent on a parasite specific myosin, a highly divergent actin and plasma membrane proteins, adhesins that link the substrate to the actomyosin motor. We want to understand the molecular and biophysical basis that underlies the motility of sporozoites to eventually be able to block it. Consequently, we developed methods that allow a systematic probing of key variables important in motility in order to reveal the basic mechanisms of sporozoite locomotion and to screen for small molecules that inhibit motility. Using these assays, we made a number of groundbreaking observations on the cellular and molecular level that gave new insights into the mechanisms of sporozoite adhesion and motility. For example, the dynamic, actin-dependent turnover of adhesion sites was found to be a key factor in sporozoite motility. It is our ultimate goal to understand sporozoite motility to a degree that we can provide a comprehensive dynamic model of sporozoite movement. With the current proposal we aim at unravelling the initial molecular events leading to sporozoite motility focussing on three different adhesins that are known or suspected to be involved in motility. We hypothesize that outside-in signalling leading to actin rearrangements originates from the formation of homo- or heterodimers between these adhesins. Additionally we suggest that inside-out signalling contributes to modulation of adhesion strengths mediated by these adhesins. To test these hypotheses we will generate recombinant parasites that lack two adhesins or express fluorescently tagged adhesin fusions, chimeric or mutant adhesins and investigate these with our recently developed toolbox of novel assays.

1 453 800 €

Start date: 2012-04-01, End date: 2017-03-31

Spectrum analysis and vector network analysis are enabling technologies for component development throughout the microwave and millimeter wave band. Due to the lack of affordable electronics for frequencies above 100 GHz, vector network analyzers (VNAs) have to use frequency extenders to reach into the THz frequency band (100 GHz-10 THz). The bandwidth of frequency extended electronic systems is restricted to about 50%. Several extender setups have to be used for larger spans, requiring realignment and tedious recalibration. Further, extenders become increasingly expensive the higher the THz frequency and are, therefore, barley used. Electronic spectrum analyzers face similar problems as VNAs. Only a few examples of highly expensive photonic, pulsed frequency comb-based systems have been demonstrated. Affordable, large bandwidth commercial THz metrology tools are missing so far. This proposal aims for the development of photonic THz characterization tools based on telecom-wavelength compatible photomixing technology to satisfy this need: 1.) Photonic vector network analysers (PVNAs) with extreme frequency coverage will be realized by two approaches: a) A planar, on-chip, and broadband dielectric waveguide topology with integrated photomixers for the realization of a continuous-wave (CW) two-port PVNA, covering at least 100 GHz to 1.1 THz in a single setup. b) A pulsed, free space photonic two-port VNA for frequency extension towards 5 THz. 2.) CW photonic THz spectrum analyzers (PSAs) with a frequency coverage of at least 50 GHz -1.1 THz and a simple extension towards 2.7 THz. This system will be realized both free space and on-chip by using a photonic sweep oscillator that is mixed with the signal to be investigated and down-converted by a room-temperature operating THz detector. These systems will provide a solid basis for THz component development. The long term goal beyond this proposal is a competence center for THz device engineering.

1 500 000 €

Start date: 2017-06-01, End date: 2022-05-31

The Interleukin (IL)-1 family of pro-inflammatory cytokines are among the most potent pyrogens, and their excessive production can cause several auto-inflammatory syndromes. Additionally, overabundance of IL-1 cytokines can trigger, or contribute to a range of inflammatory and metabolic disorders. The expression of the key members of the IL-1 family, such as IL-1β and IL-18, is regulated at both the transcriptional and post-transcriptional levels. IL-1β and IL-18, are produced as inactive precursors, which require activation of caspase-1 by the inflammasomes for their maturation and release by from cells, occasionally at the cost of caspase-1 mediated-cell death. We have recently discovered that inflammasomes are released into the extracellular space where they remain active after the demise of activated cells, and that extracellular inflammasomes can amplify inflammation by sustaining extracellular production of IL-1β. However, the sources of extracellular pro-IL-1β are not known. Recent advances in platelet proteomics have revealed that these non-nucleated cells are able to produce their own cytokines, including soluble IL-1β and membrane-bound IL-1α, and are able to significantly magnify IL-1 production by immune cells. As platelets outnumber leukocytes by several folds, they could potentially be the major source of extracellular inflammasomes in the body, or be a major producer of IL-1 precursors that are cleaved by extracellular inflammasomes released from dying immune cells. In this proposal, we will investigate the mechanism(s) by which platelets produce IL-1, and the specific contribution of platelet-derived IL-1 to sterile inflammation, or host resistance to bacterial and viral infection. We believe that a deeper understanding of platelet-IL-1 and their interaction with immune cells during sterile inflammation, or infection might help to uncover new targets for immune-therapies.

1 488 854 €

Start date: 2017-03-01, End date: 2022-02-28

During the last decade, audio-visual communication has shaped the way humans interact with technical systems or other humans. During the next decade, haptic communication has the potential to further augment human-to-human and human-to-machine interaction. With recent advances in Virtual Reality, Man-Machine Interaction, Telerobotics, Telepresence, and Telemanipulation, the processing and communication of haptic signals are rapidly gaining in relevance and are becoming an enabling technology for many novel fields of application. The objective of this proposal is to investigate fundamental methods and technologies for the efficient processing and communication of haptic signals. We will develop a mathematical model of human haptic perception which will be instrumental in ensuring that introduced distortions stay below human perception thresholds. One of the main goals of this work is to leverage the model of human haptic perception for efficient lossy compression of haptic signal streams. We will study haptic signal processing and communication both from a theoretical point of view but also experimentally by designing, implementing and evaluating haptic interaction testbeds. The performance of the proposed haptic processing and communication methods will be analyzed both objectively and subjectively. With our work plan, we see the opportunity to establish a de facto standard for future haptic data communication.

1 489 000 €

Start date: 2011-01-01, End date: 2015-12-31

Quorum sensing (QS) is a bacterial cell–cell communication process involving the production, release, and detection of extracellular signal molecules called autoinducers. QS is key to all microbiology as it enables otherwise solitary bacteria to coordinate complex cooperative tasks such as biofilm formation and pathogenesis. Consequently, targeting QS is a promising new concept for antimicrobial therapy. However, for this concept to become reality, we must first identify QS systems in pathogenic bacteria, discover the relevant autoinducers and study the underlying regulatory principles. I recently identified a new QS pathway in Vibrio cholerae, the causative agent of cholera disease. The autoinducer of the system is DPO (3,5-dimethylpyrazin-2-ol), a new molecule to biology and the first pyrazine involved in QS. DPO production is widespread among microbes including pathogenic and commensal bacteria. V. cholerae synthesizes DPO from host mucins and our preliminary data show that DPO controls collective phenotypes, such as biofilm formation and toxin production in this major human pathogen. I therefore hypothesize that DPO connects virulence, QS and communication with the host microbiota in V. cholerae and related bacteria. The overarching goal of this project is to understand the roles of DPO in host-microbe interaction and collective behaviours. To this end, we will pursue three key research goals. First, we will study the molecular parameters underlying DPO-signalling and probe the global effects of DPO on gene expression. Second, we will focus on the role of DPO in virulence of V. cholerae and other pathogens. Third, we will probe the effect of DPO on microbial behaviours, such as swarming and biofilm formation. This combined work will provide a comprehensive model for DPO-signalling in bacteria, which will not only advance the fundamental understanding of QS-based communication strategies, but might also provide the framework for QS-inspired anti-infectives.

1 499 250 €

Start date: 2018-01-01, End date: 2022-12-31

We are constantly protected by our adaptive immune system. Its functioning requires precise control of gene expression in lymphocytes, since deregulation can cause autoimmune diseases (affecting ~5% of our population) as well as allergic reactions (~9-16%, with increasing incidence). Post-transcriptional control of gene expression is crucial in many immune decisions, however the determinants of specificity in this type of regulation are less well defined. The recently described Rc3h1 or Roquin protein prevents the development of autoimmune disease in mice. Rc3h1 destabilizes the mRNA of the inducible costimulator (ICOS), a co-receptor on T cells. ICOS is critical in the germinal center reaction in which T cell help selects B cells making high affinity antibodies. However, the molecular interactions of this posttranscriptional regulation and the pathways that specify such repressor/target relations are unsolved, and they are the focus of my work in this proposal. Rc3h1 is an essential factor of peripheral T cell tolerance, whereas the role of its paralog Rc3h2 has not been addressed. We have recently shown that Rc3h1 is an RNA binding-protein that recognizes the 3’UTR of ICOS mRNA. Our preliminary data suggest that Rc3h2 is co-expressed in T cells and binds ICOS mRNA indistinguishably in vitro, however it does not repress ICOS. Major challenges are therefore to define how the Rc3h1/2 proteins recognize cis-elements in the RNA, which cofactors they require for repression and how these proteins exert diverse functions. My project proposes to pursue three aims: (1) to describe Rc3h1/2 target recognition in the T cell transcriptome, (2) to globally identify the essential genes in this pathway of post-transcriptional repression and (3) to analyze redundant and unique roles of Rc3h1 and Rc3h2 proteins in the mouse embryo, the hematopoietic system and in models of immunity and spontaneous development of autoimmune disease.

1 392 400 €

Start date: 2011-11-01, End date: 2016-10-31

The broad science objective of this proposal is to search for the root causes of solar magnetic activity by establishing connections and physical relationships between internal solar properties and the various components of magnetic activity in the solar interior and atmosphere. The physical processes inside the Sun are best studied with helioseismology, i.e. the observation and interpretation of solar seismic waves. Helioseismology is on the verge of a revolution with (1) the development of new techniques of data analysis and interpretation and (2) forthcoming observations by NASA’s Solar Dynamics Observatory (SDO, scheduled for launch in 2008), which represents a major technological step beyond the ESA/NASA SOHO mission: higher spatial resolution, higher cadence, and a complete view of the solar disk and the corona. I propose to develop an active program of research in local helioseismology, a relatively young science. New methods of analysis will be developed to make 3D images of the solar interior and to infer the subsurface structure of sunspots using full-waveform modeling techniques. In order to take full advantage of space-based observations, I propose to establish a computing center for helioseismology at the Max Planck Institute for Solar System Research, which will provide the infrastructure and the manpower required to process the relevant SOHO/MDI and SDO/HMI data and to deliver original science data products.

500 000 €

Start date: 2008-08-01, End date: 2013-01-31