Gas-sensing proteins play an important role in mediating biological events. Soluble guanylate cyclase (sGC) is activated when nitric oxide (NO) binds to heme Fe of sGC, and then stimulates cyclization of guanosine 5-triphosphate (GTP) to the second messenger cyclic guanosine 3,5-monophosphate (cGMP), which in turn has a direct role in the control of a variety of physiological processes in several signal transduction pathways. Disruptions in the NO/sGC/cGMP signalling pathway have been linked to a variety of diseases including congestive heart failure, stroke, hypertension and neurodegeneration. In this proposal, we will derive novel molecular insight into the heme-containing sensor domain of human sGC that is the primary receptor for NO and therefore plays a significant role in NO-signalling by employing structural and computational methods. The project will use the power of solution NMR spectroscopy and enhanced conformational sampling computational approaches to improve our atomistic understanding for this key biological protein and to identify a representative conformational ensemble that will be used in virtual screening of chemical libraries, so as to identify new, original, and more effective compounds for the activation of sGC. This novel approach of combining NMR and computational MD data to identify receptor conformations that play a major role in biomolecular recognition before commencing the structure-based virtual screening is expected to have a major impact in the field of drug design. Throughout this fellowship, the fellow will gain invaluable experience by combining the already accumulated experience in computational biology and CADD with advanced methods using NMR and computational data for the study of biomolecular structure and dynamics. This fellowship is expected to play a pivotal role at his reaching a position of professional maturity and will contribute to his successful transition to an independent research leader.
This project aims to protect, and commercialize a new panel of transplantable mouse lung cancer cell lines with defined mutation status (MLC) for cancer research and drug discovery. In addition, we aim at disseminating and exploiting a novel method for generating an unlimited pool of such lines from various strains of mice. Human lung cancer is characterized by a variety of mutations in oncogenes (i.e., KRAS) and tumor suppresors (i.e., TRP53), which largely determine whether lung tumors respond to a given therapeutic regime. Human lung cancer cell lines are invaluable for in vitro studies, but need to be propagated in immunodeficient mice, compromising the validity of the results obtained. A panel of syngeneic MLC with a defined and a genetically malleable battery of mutated oncogenes would allow more physiologically relevant studies, would help accelerate research and drug discovery in the field, and would generate substantial interest in the academia and the industry. For the purposes of mother project FP7-IDEAS-ERC-StG-2010-KRASHIMPE-260524 aimed at studying KRAS-driven host-tumor interactions, we derived such MLC lines from the lungs of mice using exposure to tobacco carcinogens or genetic oncogenesis. We request funding to i) characterize MLC lines to show proof-of-concept data that they can be used for drug and oncogene discovery; ii) assemble them into a marketable product; iii) protect these discoveries; iv) assess their market potential; v) attract potential interested parties; and vi) commercialize this new product. We hope the results of this project will speed up investigation and drug discovery by shortening the presently wide time interval between cancer wet bench research and clinical applications.
The state-of-the-art review in seismic retrofit of existing reinforced-concrete (RC) buildings indicates that a technology that is non-disruptive and easy to implement, achieves simultaneous control of drifts and accelerations, and overcomes major issues related to low concrete strength, poor reinforcement details, and vulnerable RC columns, has never been described in the literature or in seismic design codes (e.g. Eurocode 8). The ambitious main objective against the background of the state-of-the-art of the project is to develop such a retrofit technology. In particular, the project will develop a non-disruptive retrofit scheme using an external, modular, steel frame as a facade close and in parallel connected to frames of the existing RC building. The external steel frame will have chevron braces to support energy dissipation devices, and, connectors to achieve horizontal coupling with the existing RC building. Strategically, the energy dissipation devices will be visco-plastic dampers, i.e. novel devices that will offer visco-elastic damping output under low-to-moderate earthquake intensities and friction damping output with a predefined limit on their peak force under high seismic intensities. The project will develop sophisticated yet practical structural details and a simplified seismic design procedure for the external steel frame. All these will be achieved through a carefully planned integrated experimental and numerical research program involving constitutive modelling, nonlinear finite element analysis, and shaking table tests. The proposed retrofit scheme constitutes a solid contribution to earthquake engineering that is expected to raise major international scientific and industrial interest.
The reusability of steel structures after fire under seismic combinations of actions is particularly important within a variety of disciplines including ecology, sociology, and engineering. The best solution is to assess the reparability and retrofit the fire-exposed steel structures for desired seismic performance on a scientific knowledge base. The proposed PBE-FireSeismicRes project will develop a performance-based engineering framework for assessing and enhancing the seismic resilience of fire-exposed steel structure that is expected to raise major international scientific and industrial interest. This framework will be sophisticated and practical. First, collaborative research efforts will be presented to develop high-fidelity computational models of fire-exposed steel structures to assess the seismic fragility of these structures with various fire and earthquake scenarios. Second, seismic protective technologies will be developed to promote the application of the technologies and design to restore and upgrade the seismic resilience of deficient fire-exposed steel structures. Following this, design criteria, design methodology, and risk-based assessment approach will be established within the performance-based engineering framework to promote the reusability of fire-exposed steel structures. Together, the research outcomes from this project bear the potential to significantly advance the state of art in better safeguarding the built environment against earthquake hazards.