NIHRDataInsights/HRCSData huggingface dataset:
Title: Structural studies of atomic interactions in membranes: bridging the gap between physics and membrane biology
Funder: Engineering and Physical Sciences Research Council

Abstract: The focus of this work is observe the atomic and molecular interactions between molecules which comprise cell membranes. Cellular membranes are the gate-keepers of life. Life has evolved from single-celled organisms to more complex multi-cellular organisms partially because of the compartmentalization of cell membranes. In the last century one of the great challenges was to decode DNA - the molecular blueprint for life. In the next century one of the greatest challenges is to understand how membranes are formed and function; as they are not only everywhere but are also necessary to sustain life. Cell membranes control what can go into and out of the cell, the so-called 'molecular traffic' acting as gate-keepers. This role is important in controlling disease, disease and nutritional balance in different parts of the human body. This research proposes to look at the interactions between the molecules which make up biological membranes on the atomic scale, where one can see how individual atoms in different molecules interact with one another. This is important because it reveals the details of interactions and can inform us about how these interactions take place. The techniques which will be used to see the atomic structure of membranes are neutron scattering techniques using the UK ISIS neutron facilities which are located at Rutherford Appleton Laboratories in Oxfordshire (UK) and managed by the UK government funded Science and Technology Facilities Council (STFC). Measurements of these molecules using neutrons shows the details of interactions between the different atoms present. Another technique which will be used is Nuclear Magnetic Resonance (NMR) which allows for different atomic aspects of the membrane to be seen. Combing this with computer models, we will be able to build a structure of the membrane which is atomically accurate. Understanding membranes is important for a variety of reasons. First they are present in all plants and animals and indeed are one of the reasons that life exists. Understanding the structure of membranes is also needed to understand the regulation of cell activity and so this research will have a major impact on our understanding of the mechanisms of transport across the cell membrane, such as drugs and nutrients. The results of the study will aid descriptions of many of the things that membranes do, such as signal transduction - which is important in passing messages between brain cells and the body via molecules called neurotransmitters, the passage of drugs into cells and the effect of external influences on cells from toxins and antimicrobial agents.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Dream Fellowship: Promoting Design for Wellbeing (DfW) in the Built Environment
Funder: Engineering and Physical Sciences Research Council

Abstract: My vision for the Dream Fellowship is to promote design for wellbeing (DfW) in the built environment. Architectural education and practice generally views architecture as 'art', values originality above all else and rarely acknowledges ordinary people's experiences. Engineers are trained to high levels of technical competence but have little understanding of how their work impacts users. In the late 19th and early 20th centuries, the link between built environments and health and wellbeing was undisputed (see the many articles on housing in the Lancet at this time), but over the last century health provision has become increasingly focused on clinical treatment of illness through the NHS. However, the challenges of the 21st century demand change. Global warming and other environmental issues have led to the growth of sustainable housing design and promotion of 'sustainable communities'. It is now acknowledged that sustainable development must take into account social issues such as health and wellbeing in order to be effective, and environmental solutions are likely to fail unless they address users' aspirations. At the same time, health service providers are beginning to see that built environments may play a role in the prevention of ill-health. I see the need for a new approach to design - one that a) aims to optimise people's health and wellbeing, b) uses evidence of what works and what doesn't, and c) considers the 'whole system', integrating the range of built environment specialisms I believe we can establish a new skill-base which transcends traditional disciplinary boundaries and combines the expertise of the architect, engineer, urban designer, planner, occupational therapist and public health practitioner. Through the Fellowship I will pursue two overall goals: To facilitate new directions in DfW research in order to build a reliable, useable evidence base for policy and practice; To facilitate a cultural shift in both built environment and health education and practice towards this integrated, informed DfW approach. I will achieve the following: 1. Bring together key academics working in the DfW field within different disciplines, improving integration between them; 2. Establish effective links between academics and practitioners in the field, through creation of a 'community of practice', to facilitate research and knowledge transfer; 3. Identify best practice, innovative methods and new directions, to improve both the quality and quantity of research in the field; 4. Develop a benefits case for the DfW agenda to convince stakeholders of its value; 5. Consolidate existing findings for use by policy makers and practitioners as coherent evidence for DfW; 6. Establish the framework for training of a new generation of designers, equipped with the skills to implement DfW in practice.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: GENERIC HEALTH RELEVANCE
Title: Modelling composition-solubility relationships in bio-active phosphate glasses
Funder: Engineering and Physical Sciences Research Council

Abstract: The manufacture of biocompatible materials for tissue replacement is a central theme in the fields of biomedicine and tissue engineering research. Natural sources of bone graft material are compromised by availability and cost, both from the individual patient as autograft and from other donors as allograft. "Third generation" bioactive implant materials, which play an active role in tissue regeneration and degrade after the tissue has healed, have been remarkably successful in many clinical applications, especially in dental and orthopaedic fields. Among the third-generation biomedical materials, phosphate-based bio-active glasses (PBGs) are becoming increasingly popular owing to their unique properties: (i) their composition is chemically related to the surrounding tissue; (ii) they dissolve completely in aqueous media; (iii) their dissolution rate can be controlled by changing the composition of the phosphate-sodium-calcium glass. The solubility of the PBGs, which is arguably their most important property to be exploited in biomedical applications, can thus be tailored to suit the end application. As the solubility of a glass is linked to its atomic-level structure, insight into the P2O5 network structure at the molecular level; the effect of varying concentrations of calcium and sodium and other cations on the network; and the dominant surface and dissolution processes, are of fundamental interest to the design of phosphate glass compositions for applications in tissue engineering. However, a common problem in the investigation of these materials, generally related to their amorphous nature, is the lack of detailed information on the microscopic structure of the glasses and how this structure is affected by the different ions making up the glass composition. This research proposal therefore aims to develop robust models to provide quantitative insight at the atomic level into the structures, physico-chemical properties and solubilities of a range of phosphate-based bioglasses as a function of their composition.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE
Title: Shell inspiration: turning nature’s secrets into engineering solutions
Funder: Engineering and Physical Sciences Research Council

Abstract: The properties of a material are strongly affected by its microscopic structure, a phenomenon that can often be seen in nature. This is clearly evident in the shells of molluscs such as mussels. These seashells exhibit magnificently diverse shapes, patterns and colours. In addition, they have a toughness similar to steel whilst being much lighter. These fascinating characteristics are the result of the way that shells are made from organised building blocks of calcium carbonate (the mineral found in chalk). In nature, the combination of these building blocks is exquisitely controlled throughout growth. The ability to use nature's secrets learned from shell growth would be invaluable in manufacturing high performance materials with unprecedented properties. To realise this, we first need to learn how nature controls the formation and assembly of the building blocks of a shell - calcium carbonate. In this proposal, we will develop a new approach to enable an in-depth understanding of this natural controlling process, and then exploit the knowledge for producing novel material that are inspired by nature. At the core of our approach is the "Electronically Programmable Microfluidic Fountain Array" (EPMFA), a tool to create biomimetic conditions for the investigation. The EPMFA will enable us to control all of the aspects of organising building blocks (such as calcium carbonate), from features only visible with the best microscopes; through to the overall shape and size of the material that we are creating. We will start off with a focus on a single example material, Mother-of-Pearl, and then exploit what we have learnt to create novel structures based on the same building blocks. This new material will be specifically designed so that it could be used as part of a medical implant, with properties that would greatly benefit bone reconstruction or joint replacement. We envisage the knowledge gained will significantly enhance our abilities in creative manufacturing, and will benefit a very wide range of areas, from medicine to climate change. By using building blocks beyond calcium carbonate, our techniques will let us design and manufacture new materials with unique combinations of optical, magnetic, electronic, chemical and mechanical properties. The uses for these materials will be almost endless.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE
Title: CCP-BioSim: Biomolecular simulation at the life sciences interface
Funder: Engineering and Physical Sciences Research Council

Abstract: Biomolecular simulation is a vibrant and growing area, making increasingly significant contributions to structural and systems biology. Physics-based simulations complement experiments in building a molecular level understanding of biology: they can test


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Optical and Acoustic Imaging for Interventional Device Guidance
Funder: Engineering and Physical Sciences Research Council

Abstract: Medical needles are central to a wide range of diagnostic and therapeutic interventions, including tissue biopsies and injections of anaesthesia. Accurately and efficiently reaching deep tissue targets can be very challenging. Many needle insertions are performed with ultrasound imaging systems that are exterior to the body, and with the sense of touch that is relayed via the needles to a physician's hands. These techniques are often insufficient for directly detecting the tissue targets, however, and consequently there is a risk of inaccurate needle placement. For instance, with biopsies of the prostate, the suspected cancerous lesions may not be visible with ultrasound imaging, and consequently the biopsies may be obtained from incorrect locations. As a new Lecturer at the Department of Medical Physics and Bioengineering at UCL, one of my primary objectives is to transform medical needles so that they that can provide molecular information about tissue and thereby significantly improve the accuracy of needle-based procedures. Leveraging recent advances in optical telecommunications technologies, these needles will deliver brief light pulses to tissues at their tips. By virtue of the photoacoustic effect, absorption of light pulses will generate sound waves that can be detected and converted into images of molecular absorption in real-time. The research programme kick-started by an EPSRC First Grant will ultimately lead to the development of a broad range of medical devices that could directly detect tissue targets and critical structures to improve clinical outcomes and decrease the risks of complications.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE
Title: Complementary Gel and Microemulsion Strategies for Pharmaceutical Solid Form Control
Funder: Engineering and Physical Sciences Research Council

Abstract: The issue of the solid form of drug substances is of key importance to the UK pharmaceutical industry. Different crystal forms have different bioavailability and solubility characteristics, and the crystal shape (needle, plate, block etc.) significantly affects processing and tabletting behaviour. Moreover discovery and patenting of all polymorphic forms is a necessary part of current drug discovery research. There have been a number of high profile cases where failure to identify the most stable crystal form of a drug has led to severe formulation problems in manufacture. This is often because the stable form has a high nucleation energy barrier so is very slow to nucleate and only appears late in the production process, resulting in huge encumbant cost. Drug solid form is a major issue for the UK economy and tremendous investments focus on calculating crystal structure and on empirical polymorph screening by a wide variety of crystallisation techniques. This project will use the complementary techniques of crystallisation from microemulsions and crystallization within tailored low molecular weight organogels to provide a general solid form discovery method as well as a means of influencing crystal shape and surface characteristics that will greatly enhance both the robustness and scope of present polymorph screening techniques in the pharmaceutical industry. By use of the 3D-nanoconfinement in microemulsions to initially limit the crystal nucleus size, the novel microemulsion method allows systematic identification and preparation of the most thermodynamically stable polymorphic form. Crystallisation in individually tailored (i.e. chemically complementary to a particular drug substance), low molecular weight gels, will allow isolation and identification of kinetic polymorphic forms and offers the advantage of heteronucleation sites that can catalyse the growth of forms that are very slow to begin crystallising. Between them, therefore, the two crystallisation strategies offer a step change in the systematic approach to pharmaceutical polymorph screening and identification strategies and hence solid form discovery and selection.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE
Title: Complexity-Generating Hydration Reactions via Metal-Catalysed Reaction of Boronic Acids with Alkenes
Funder: Engineering and Physical Sciences Research Council

Abstract: Simple organic molecules containing carbon-carbon double bonds, known as alkenes, are widely available bulk chemicals that serve as basic starting materials for the synthesis of a wide range of more complex molecules with useful properties - pharmaceuticals, fine chemicals, agrochemicals, polymers, etc. In this proposal we outline new catalytic strategies for the direct conversion of alkenes into complex molecular structures. In each case, a novel sequence of reactions is initiated via the formal addition of a molecule of water across the carbon-carbon double bond of the alkene (a hydration reaction). The reaction of water with an alkene can be difficult to accomplish as many alkenes do not dissolve in water. It is usually achieved using either strong acids (e.g. sulfuric acid) or mercury salts (which are very toxic). In this research we will employ a new strategy based upon previous work from our laboratory in which the water molecule is attached to an organic boron-containing compound, enabling it to be 'dissolved' in an organic solvent and to react more readily in the presence of a suitable catalyst (In this project more efficient and considerably less toxic catalysts based around metals such as palladium, platinum and gold will be used - our preliminary experiments have demonstrated that such catalysts are effective). This strategy is potentially very powerful as the boron atom can be used in further (post-hydration) chemical reactions to construct complex products. These new reaction strategies will be of use for the synthesis of a wide range of products including molecules of interest for screening against disease targets in medical research. This will enable us to build up collaborations with appropriate biologists in order to apply our new discoveries in the development of new medical treatments.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE
Title: Thiyl Radicals and Isocyanides: A New Approach Towards Biologically Active Heterocycles
Funder: Engineering and Physical Sciences Research Council

Abstract: The pharmaceutical industry is under intense pressure to improve the supply of new therapeutics whilst at the same time, reducing both cost and transition-time from discovery to application. This problem is hard to resolve without the development of new synthetic methodology or new technology and the proposed research will address both aspects of this. Most medicines and agrochemicals are based on heterocycles and as a result, the search for new efficient methodology for their syntheses that avoids the use of protecting groups is essential. One key neglected class of reaction that is an obvious solution to this problem is radical chemistry, which uses mild conditions without the need for protecting groups. However, radical chemistry has received little attention from the pharmaceutical industry because the majority of reactions involve the use of organotin derivatives and are often carried out at high dilution. Whilst this is acceptable for the gram amounts required for medicinal chemistry, this is clearly impractical when moving to the kilogram quantities required in process chemistry. Synthetic routes are often redesigned and radical chemistry removed to minimise the purification steps required to remove the toxic by-products. To address this challenge, flow chemistry technology has emerged as a viable means for performing many types of chemical transformations as reactions can be run over time or in parallel, to produce either gram or kilogram quantities. Therefore, the transition from medicinal to process laboratories has become less cost-intensive and flow-chemistry has attracted considerable attention from the pharmaceutical industry. Unfortunately, despite its potential, radical chemistry has not undergone the same transition in the pharmaceutical industry due to its reliance on organotin compounds. In preliminary studies, we have demonstrated that a non-toxic sulfur radical/ isocyanide based cyclisation of tricyclic heterocycles is viable and that it is a credible replacement for organotin derivatives. In the proposed research, we will explore the scope of this process to synthesise a range of key biologically active heterocycles, including anti-cancer compounds currently undergoing clinical trials. In conjunction with this, we will apply our chemistry to flow reactor technology to demonstrate that radical chemistry can be revisited as a method to produce larger scale quantities of material for the pharmaceutical industry.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE
Title: Restricted Diversity; Constrained Diversity-Oriented Synthesis
Funder: Engineering and Physical Sciences Research Council

Abstract: The UK is at the forefront of the worldwide pharmaceutical industry, which develops new medicines for many diseases, and benefits the British economy through income, employment, expertise and major investment. The UK pharmaceutical industry directly employs around 70,000 people and typically contributes £10 billion to the UK's GDP. Figures for 2007 show that the industry invested a total of £3.9 billion in UK research and development, and that exports of pharmaceutical products from the UK totalled £14.6 billion, creating a trade surplus in pharmaceutical products of £4.3 billion. This is an important industry to support with academic research. The industry is concerned with the creation of small molecules. Pharmaceutical drugs are small molecules. The discovery of small molecules that have specific properties or functions is clearly important for scientific progress that will impact on everyday life. Unfortunately, there is a serious problem in the development of new drugs. Drug discovery has been hampered by a high rate of attrition of clinical candidates. This has been ascribed to the clinical candidates not having the correct properties or binding profiles. This proposal aims to exemplify new strategies to access efficiently and discover novel small molecules within a desired range of properties or binding profiles that are directly relevant to the pharmaceutical industry. This strategy has been termed constrained diversity-oriented synthesis. The project will involve the development of new chemistry, the synthesis of new small molecules, differential assessment of restricted diversity and the discovery of biologically active compounds and potential chemotherapeutic agents. The approach will lay the scientific and technological foundations for the development of protein-protein interaction modulation as a tool for chemical biology and molecular therapeutics. The proposed work has the potential to transform current approaches to drug discovery, and to rally extend the repertoire of tools available for chemical biology. Small molecules are essential to everyday life. They have importance beyond the pharmaceutical industry, since plastics derive from small molecules, hydrocarbon fuels are small molecules, etc. Therefore, our research has the potential to impact widely on health and quality of life.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES;5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE