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Project acronym BINDING FIBRES
Project Soluble dietary fibre: unraveling how weak bonds have a strong impact on function
Researcher (PI) Laura Nyström
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Summary Dietary fibres are recognized for their health promoting properties; nevertheless, many of the physicochemical mechanisms behind these effects remain poorly understood. While it is understood that dietary fibres can associate with small molecules influencing, both positively or negatively their absorption, the molecular mechanism, by which these associations take place, have yet to be elucidated We propose a study of the binding in soluble dietary fibres at a molecular level to establish binding constants for various fibres and nutritionally relevant ligands. The interactions between fibres and target compounds may be quite weak, but still have a major impact on the bioavailability. To gain insight to the binding mechanisms at a level of detail that has not earlier been achieved, we will apply novel combinations of analytical techniques (MS, NMR, EPR) and both natural as well as synthetic probes to elucidate the associations in these complexes from macromolecular to atomic level. Glucans, xyloglucans and galactomannans will serve as model soluble fibres, representative of real food systems, allowing us to determine their binding constants with nutritionally relevant micronutrients, such as monosaccharides, bile acids, and metals. Furthermore, we will examine supramolecular interactions between fibre strands to evaluate possible contribution of several fibre strands to the micronutrient associations. At the atomic level, we will use complementary spectroscopies to identify the functional groups and atoms involved in the bonds between fibres and the ligands. The proposal describes a unique approach to quantify binding of small molecules by dietary fibres, which can be translated to polysaccharide interactions with ligands in a broad range of biological systems and disciplines. The findings from this study may further allow us to predictably utilize fibres in functional foods, which can have far-reaching consequences in human nutrition, and thereby also public health.
Dietary fibres are recognized for their health promoting properties; nevertheless, many of the physicochemical mechanisms behind these effects remain poorly understood. While it is understood that dietary fibres can associate with small molecules influencing, both positively or negatively their absorption, the molecular mechanism, by which these associations take place, have yet to be elucidated We propose a study of the binding in soluble dietary fibres at a molecular level to establish binding constants for various fibres and nutritionally relevant ligands. The interactions between fibres and target compounds may be quite weak, but still have a major impact on the bioavailability. To gain insight to the binding mechanisms at a level of detail that has not earlier been achieved, we will apply novel combinations of analytical techniques (MS, NMR, EPR) and both natural as well as synthetic probes to elucidate the associations in these complexes from macromolecular to atomic level. Glucans, xyloglucans and galactomannans will serve as model soluble fibres, representative of real food systems, allowing us to determine their binding constants with nutritionally relevant micronutrients, such as monosaccharides, bile acids, and metals. Furthermore, we will examine supramolecular interactions between fibre strands to evaluate possible contribution of several fibre strands to the micronutrient associations. At the atomic level, we will use complementary spectroscopies to identify the functional groups and atoms involved in the bonds between fibres and the ligands. The proposal describes a unique approach to quantify binding of small molecules by dietary fibres, which can be translated to polysaccharide interactions with ligands in a broad range of biological systems and disciplines. The findings from this study may further allow us to predictably utilize fibres in functional foods, which can have far-reaching consequences in human nutrition, and thereby also public health.
Project acronym CELLCONTROL
Project Synthetic regulatory circuits for programmable control of cell physiology
Researcher (PI) Yaakov Benenson
Summary The newly emerging discipline of Synthetic Biology holds the promise of radically changing the way we probe, control and augment living matter from single cells to entire organisms, and revolutionize basic biological research, biotechnology, and medicine. However, practical work toward these important goals is still in its infancy, in part because concrete approaches to achieve rational control of cell physiology are currently lacking. In order to advance this vision, here we propose a detailed strategy toward engineered regulatory circuits that read out complex cellular states based on multiple biological signals, and convert this information into a desired action based on pre-programmed signal integration. If successful, our strategy will enable unprecedented level of rational intervention with the cell. Specifically, we suggest to read out cellular information as relayed by expression and activity of cell's transcription factors, proteins that control gene expression and serve as major regulators of cell fate and cell response to transient stimuli. The readout will be accomplished with the help of specially-designed sensor promoters that will in turn drive the expression of engineered microRNA molecules. Those molecules in turn will converge on a small number of response elements in engineered downstream transcripts, implementing highly-flexible and programmable logic integration of the original transcription factor signals (Rinaudo et al, Nature Biotechnology, 2007 and Leisner et al, Nature Nanotechnology, 2010). We propose a stepwise bottom-up construction strategy whereby we first design, test and optimize sensor promoters for individual TFs, next we integrate them into large networks, and finally we show how to utilize these networks as prototype selective anti-cancer therapies. To validate our approaches, we will use human cancer cell lines as a model system.
The newly emerging discipline of Synthetic Biology holds the promise of radically changing the way we probe, control and augment living matter from single cells to entire organisms, and revolutionize basic biological research, biotechnology, and medicine. However, practical work toward these important goals is still in its infancy, in part because concrete approaches to achieve rational control of cell physiology are currently lacking. In order to advance this vision, here we propose a detailed strategy toward engineered regulatory circuits that read out complex cellular states based on multiple biological signals, and convert this information into a desired action based on pre-programmed signal integration. If successful, our strategy will enable unprecedented level of rational intervention with the cell. Specifically, we suggest to read out cellular information as relayed by expression and activity of cell's transcription factors, proteins that control gene expression and serve as major regulators of cell fate and cell response to transient stimuli. The readout will be accomplished with the help of specially-designed sensor promoters that will in turn drive the expression of engineered microRNA molecules. Those molecules in turn will converge on a small number of response elements in engineered downstream transcripts, implementing highly-flexible and programmable logic integration of the original transcription factor signals (Rinaudo et al, Nature Biotechnology, 2007 and Leisner et al, Nature Nanotechnology, 2010). We propose a stepwise bottom-up construction strategy whereby we first design, test and optimize sensor promoters for individual TFs, next we integrate them into large networks, and finally we show how to utilize these networks as prototype selective anti-cancer therapies. To validate our approaches, we will use human cancer cell lines as a model system.
Project acronym DeNovoImmunoDesign
Project Computational Design of Novel Functional Proteins for Immunoengineering
Researcher (PI) BRUNO EMANUEL FERREIRA DE SOUSA CORREIA
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Summary Finely orchestrated protein activities are at the heart of the most fundamental cellular processes. The rational and structure-based design of novel functional proteins holds the promise to revolutionize many important aspects in biology, medicine and biotechnology. Computational protein design has led the way on rational protein engineering, however many of these designed proteins were solely focused on structural accuracy and completely impaired of function. DeNovoImmunoDesign proposes novel computational design strategies centered on the exploration of de novo protein topologies and the use of structural flexibility with the ultimate goal of designing functional proteins. The proposed methodologies aim to solve a prevalent problem in computational design that relates to the lack of optimal design templates for the optimization of function. By expanding beyond the known protein structural space, our approaches represent new paradigms on the design of de novo functional proteins. DeNovoImmunoDesign will leverage our new methodologies to design functional proteins with rational approaches for two crucial biomedical endeavors - vaccine design and cancer immunotherapy. Our strategy for vaccine design is to engineer structure-based epitope-focused immunogens to elicit potent neutralizing antibodies – a requirement for vaccine protection. The underlying basis of cancer immunotherapy is the inhibition of key protein-protein interactions - an arena where rational design is lagging. To meet this central need we will develop innovative approaches to design new protein binders for cancer immunotherapy applications. DeNovoImmunoDesign is a multidisciplinary proposal where computation is intertwined with experimentation (biochemistry, structural biology and immunology). Our unique competences and groundbreaking research have all the components to translate into transformative advances for both basic and applied biology through innovations in rational protein design.
Finely orchestrated protein activities are at the heart of the most fundamental cellular processes. The rational and structure-based design of novel functional proteins holds the promise to revolutionize many important aspects in biology, medicine and biotechnology. Computational protein design has led the way on rational protein engineering, however many of these designed proteins were solely focused on structural accuracy and completely impaired of function. DeNovoImmunoDesign proposes novel computational design strategies centered on the exploration of de novo protein topologies and the use of structural flexibility with the ultimate goal of designing functional proteins. The proposed methodologies aim to solve a prevalent problem in computational design that relates to the lack of optimal design templates for the optimization of function. By expanding beyond the known protein structural space, our approaches represent new paradigms on the design of de novo functional proteins. DeNovoImmunoDesign will leverage our new methodologies to design functional proteins with rational approaches for two crucial biomedical endeavors - vaccine design and cancer immunotherapy. Our strategy for vaccine design is to engineer structure-based epitope-focused immunogens to elicit potent neutralizing antibodies – a requirement for vaccine protection. The underlying basis of cancer immunotherapy is the inhibition of key protein-protein interactions - an arena where rational design is lagging. To meet this central need we will develop innovative approaches to design new protein binders for cancer immunotherapy applications. DeNovoImmunoDesign is a multidisciplinary proposal where computation is intertwined with experimentation (biochemistry, structural biology and immunology). Our unique competences and groundbreaking research have all the components to translate into transformative advances for both basic and applied biology through innovations in rational protein design.
Project acronym ErgOX
Project Enzymology of oxidative sulfur transfers
Researcher (PI) Florian Peter Seebeck
Host Institution (HI) UNIVERSITAT BASEL
Summary Oxidative stress causes cancer, cardiovascular, neurodegenerative and infective disease. Much of cellular oxidative stress is mediated, communicated, mitigated or amplified by a complex system of sulphur containing small metabolites or protein based cysteines. Characterization of key players and reactions in this network is crucial for preventive and therapeutic interventions. I propose a new perspective on sulphur biochemistry. The reactivity of sulphur with the oxidative stressors superoxide, peroxides or hydroxyl radicals is well established, but far less is known about reactions between sulphur and molecular oxygen. I shall demonstrate that this reaction is fundamental to cellular life, and how advances in this field provide new options in medicine, biotechnology and the food industry. Assisted by a team of three PhD students and a postdoctoral researcher I intend to establish this new research field by identification, characterization and engineering of enzymatic activities which catalyse oxidative carbon-sulfur bond formation and cleavage. Specific systems in this study include the biosynthetic enzymes for ergothioneine, sparsomycine and alliin, all of which are sulphur containing secondary metabolites with potent activities on cellular functions.
Oxidative stress causes cancer, cardiovascular, neurodegenerative and infective disease. Much of cellular oxidative stress is mediated, communicated, mitigated or amplified by a complex system of sulphur containing small metabolites or protein based cysteines. Characterization of key players and reactions in this network is crucial for preventive and therapeutic interventions. I propose a new perspective on sulphur biochemistry. The reactivity of sulphur with the oxidative stressors superoxide, peroxides or hydroxyl radicals is well established, but far less is known about reactions between sulphur and molecular oxygen. I shall demonstrate that this reaction is fundamental to cellular life, and how advances in this field provide new options in medicine, biotechnology and the food industry. Assisted by a team of three PhD students and a postdoctoral researcher I intend to establish this new research field by identification, characterization and engineering of enzymatic activities which catalyse oxidative carbon-sulfur bond formation and cleavage. Specific systems in this study include the biosynthetic enzymes for ergothioneine, sparsomycine and alliin, all of which are sulphur containing secondary metabolites with potent activities on cellular functions.
Project acronym MechanoIMM
Project Mechanical Immunoengineering for Enhanced T-cell Immunotherapy
Researcher (PI) Li TANG
Summary Cancer immunotherapy harnessing the power of a patient's immune system to fight cancer is transforming the standard-of-care for cancer. Adoptive cell therapy (ACT), a potent immunotherapy that directly infuses a large number of tumour-reactive T cells into patients, has elicited dramatic clinical responses in leukaemia patients recently. However, solid tumour remains a major challenge as tumour employs a number of strategies to prevent effector T cells reaching the tumour sites and attacking cancer by generating a highly immunosuppressive microenvironment. Current strategies are focused on controlling the immune system or the microenvironment using biochemical immunomodulatory reagents to enhance T cell based immunotherapy. Approaches exploiting biophysical and mechanical cues for immunomodulation are largely underappreciated. In this proposal, we aim to exploit mechanical immunoengineering strategies through biophysical cues to develop novel immune related treatments to enhance the efficacy and safety of adoptive T cell therapy for cancer. We will first develop a mechano-training approach to promote the T cell infiltration into tumour tissues using engineered microfluidic system for controlled force application on T cells in a high through-put manner. Second, we will develop a mechano-responsive nanoparticle delivery system to selectively deliver T-cell-supporting drugs in tumour to overcome the immune suppression in the microenvironment and enhance T cell functions for killing cancer. Third, we will develop mechano-inducible cytokine-secreting T cell therapies to augment the efficacy and minimize the toxicity of ACT by exploiting and targeting the difference in tissue stiffness between tumour and healthy tissues. This proposed project will open a new horizon for immunoengineering through biomechanical modulation of immunity for enhanced cancer immunotherapy and provide insight into the fundamentals of mechanotransduction in immune system in health and disease.
Cancer immunotherapy harnessing the power of a patient's immune system to fight cancer is transforming the standard-of-care for cancer. Adoptive cell therapy (ACT), a potent immunotherapy that directly infuses a large number of tumour-reactive T cells into patients, has elicited dramatic clinical responses in leukaemia patients recently. However, solid tumour remains a major challenge as tumour employs a number of strategies to prevent effector T cells reaching the tumour sites and attacking cancer by generating a highly immunosuppressive microenvironment. Current strategies are focused on controlling the immune system or the microenvironment using biochemical immunomodulatory reagents to enhance T cell based immunotherapy. Approaches exploiting biophysical and mechanical cues for immunomodulation are largely underappreciated. In this proposal, we aim to exploit mechanical immunoengineering strategies through biophysical cues to develop novel immune related treatments to enhance the efficacy and safety of adoptive T cell therapy for cancer. We will first develop a mechano-training approach to promote the T cell infiltration into tumour tissues using engineered microfluidic system for controlled force application on T cells in a high through-put manner. Second, we will develop a mechano-responsive nanoparticle delivery system to selectively deliver T-cell-supporting drugs in tumour to overcome the immune suppression in the microenvironment and enhance T cell functions for killing cancer. Third, we will develop mechano-inducible cytokine-secreting T cell therapies to augment the efficacy and minimize the toxicity of ACT by exploiting and targeting the difference in tissue stiffness between tumour and healthy tissues. This proposed project will open a new horizon for immunoengineering through biomechanical modulation of immunity for enhanced cancer immunotherapy and provide insight into the fundamentals of mechanotransduction in immune system in health and disease.
Project acronym PERVOL
Project Perception of Plant Volatiles
Researcher (PI) Matthias Erb
Host Institution (HI) UNIVERSITAET BERN
Summary The capacity to produce and perceive organic chemicals is essential for most cellular organisms. Plant leaves that are attacked by insect herbivores for instance start releasing distinct blends of herbivore-induced plant volatiles, which in turn can be perceived by non-attacked tissues. These tissues then respond more rapidly and more strongly to herbivore attack. One major question that constrains the current understanding of plant volatile communication is how plants perceive herbivore induced volatiles. Can plants smell danger by detecting certain volatiles with specific receptors? Or are other mechanisms at play? Answering these questions would push the boundaries of plant signaling research, as it would allow for the creation of perception impaired mutants to perform detailed analyses of the biological functions and potential agricultural benefits of plant volatile perception. My recent work identified indole as a key herbivore induced volatile priming signal in maize. As indole is produced by many different plant species and has been well studied as a bacterial volatile, it is an ideal candidate to study the mechanisms and biological functions of plant volatile perception. The key objectives of PERVOL are 1) to develop a new high-throughput plant volatile sampling system for genetic screens of indole perception, 2) to use the system to identify molecular mechanisms of indole perception and 3) to create indole perception mutants to uncover novel biological functions of volatile priming. If successful, PERVOL will set technological standards by providing the community with an innovative and powerful volatile sampling system. Furthermore, it will push the field of plant volatile research by elucidating mechanisms of herbivore induced volatile perception, generating new genetic resources for functional investigations of plant volatile signaling and testing new potential biological functions of the perception of herbivore induced volatiles.
The capacity to produce and perceive organic chemicals is essential for most cellular organisms. Plant leaves that are attacked by insect herbivores for instance start releasing distinct blends of herbivore-induced plant volatiles, which in turn can be perceived by non-attacked tissues. These tissues then respond more rapidly and more strongly to herbivore attack. One major question that constrains the current understanding of plant volatile communication is how plants perceive herbivore induced volatiles. Can plants smell danger by detecting certain volatiles with specific receptors? Or are other mechanisms at play? Answering these questions would push the boundaries of plant signaling research, as it would allow for the creation of perception impaired mutants to perform detailed analyses of the biological functions and potential agricultural benefits of plant volatile perception. My recent work identified indole as a key herbivore induced volatile priming signal in maize. As indole is produced by many different plant species and has been well studied as a bacterial volatile, it is an ideal candidate to study the mechanisms and biological functions of plant volatile perception. The key objectives of PERVOL are 1) to develop a new high-throughput plant volatile sampling system for genetic screens of indole perception, 2) to use the system to identify molecular mechanisms of indole perception and 3) to create indole perception mutants to uncover novel biological functions of volatile priming. If successful, PERVOL will set technological standards by providing the community with an innovative and powerful volatile sampling system. Furthermore, it will push the field of plant volatile research by elucidating mechanisms of herbivore induced volatile perception, generating new genetic resources for functional investigations of plant volatile signaling and testing new potential biological functions of the perception of herbivore induced volatiles.