NIHRDataInsights/HRCSData huggingface dataset:
Title: Capabilities theory and global population-level bioethics.
Funder: Wellcome Trust

Abstract: This philosophical and normative research proposes to extend the Capabilities Approach (CA) to population-level bioethics. A range of ethical questions and reasonable disagreements have arisen at the level of population health in areas such as priority-setting in health care resource allocation, equity considerations of cost-effective analysis, health measurements, social group health inequalities, global health inequalities, and so forth. As an alternative to the utilitarian philosophy which pervades both health care policy and health economics, the proposed research aims to extend the CA to population-level health ethics. The hypothesis or moral intuition is that the CA can help produce and guide health care policy that does more justice than current health maximization approaches. The CA is also likely to be more coherent in identifying social action to address population-level bioethical issues outside of health care. The research seeks to compare and contrast the CA with cost -effective analysis and health maximization; see how the CA would pursue aggregation and efficiency in health policy; see how it would measure health; and see how it would delineate societal versus individual responsibility for health. The research would be supervised by a international health economist, a social epidemiologist, and a moral and political philosopher.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Combined topographical and high speed confocal imaging systems for interdisciplinary membrane and cell biology research.
Funder: Wellcome Trust

Abstract: During the past decade a ground-breaking imaging technique has been developed, which uses the microscopic tip of a glass pipette to scan the surface of living cells or artificial membranes. In its most basic mode of operation, the Ionscope can produce an extraordinarily detailed picture of a cell surface, such that it is possible to visualize microscopic structures that underlie key aspects of normal cell function or disease. Furthermore, because a glass pipette is used to map the membrane su rface, it is also possible to deliver substances contained within the pipette or to make functional measurements at identified regions of interest. We are seeking funding, which will allow us to combine the Ionscope with another high speed imaging system, thereby further extending its capability. Specifically, the Andor confocal system is designed for high-speed imaging of events that occur inside living cells. Used in combination, this will allow, for example, the surface of a cell to be mapped at very high resolution, application of a drug at an identified location and then visualization of the consequent effects inside the cell. These systems will greatly facilitate research on disease mechanisms (e.g. Alzheimer s disease, heart failure) and novel delivery methods for therapeutic agents.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: GENERIC HEALTH RELEVANCE
Title: Aged rodent bioresource.
Funder: Wellcome Trust

Abstract: With the number of over 65s sharply increasing so is the number of chronic diseases, making the research and discovery of new treatments in this area a priority. Mouse models have greatly enhanced our understanding of human diseases and the development of new treatments. However their use in studying how to age in good health and to treat disease in older age has been limited by the costs and the time it takes for a mouse to reach old age (2 years), limiting real progress. As each researcher use s only one or two organs from each mouse, we want to establish a mouse bioresource comprising (a) a bank for the collection of the surplus organs, so that they could be readily available to other investigators to initiate new research at a reduced cost, (b) a web-based resource so that researchers can share information, collaborate and establish best practise on maintaining mice in their old age. To achieve this we have formed a consortium of 3 partners of international reputation in ageing rese arch with unique expertise in managing large mouse facilities, know-how in developing novel web-based resources and already holding a well established bank to safely store the aged mouse organs.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigation of Ca2+ and calmodulin signalling by novel calmodulin-based fluorescent probes .
Funder: Wellcome Trust

Abstract: Cells in our body respond to stimuli that derive from other parts of the body and communicated by the blood stream or nerves. When the hormone or neurotransmitter reacts with receptors on the cell surface, its signal is carried into the cell in a changed form and pattern. An important signalling entity is the calcium ion, which normally is kept at a very low level within the cell. When the cell is stimulated, the intracellular calcium levels rise and a wide variety of responses occur from muscle contraction to growth or learning depending on the type of cell. The aim of our research is to understand the principles of how the hormonal or nerve signals are correctly interpreted by the target cell. For this we have to be able to read the signals, for example by measuring the changes of calcium levels in time and space within the cell. Our proposal is to improve the sharpness of our detection of calcium to have a more precise map of its changes within the cell. When the cell is a neuron, t hese measurements will allow us to understand better how nerve cells communicate and and form memories.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing online databases and bioinformatics tools for the biology of ageing.
Funder: Wellcome Trust

Abstract: The Human Ageing Genomic Resources (HAGR) is an online collection of databases and tools for research on ageing, in particular at the genetic/genomic level (http://genomics.senescence.info). HAGR primarily consists of two databases: GenAge, a database of genes associated with ageing in model organisms and a few in humans, and AnAge, a database of ageing in animals featuring over 4,000 species and a large collection of longevity records. This project aims to 1) maintain, update and enhance HAG R. In addition to updating GenAge and AnAge, the quality and quantity of information provided will be improved. 2) Develop new tools to provide the research community with more powerful and user-friendly online tools for using HAGR, including making HAGR compatible with third-party tools. Importantly, this project aims to create two new databases: 3) a database of human longevity association studies, providing a reference for researchers working on human longevity and allowing data from multiple experiments to be combined and re-analyzed; 4) a database of genes associated with the life-extending effects of caloric restriction (CR), which consists of restricting the normal food intake of organisms and is known to extend lifespan and healthspan in multiple model organisms


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: The molecular process underlying multidrug efflux by P-glycoprotein.
Funder: Wellcome Trust

Abstract: One of the main treatment options in cancer is chemotherapy, either front-line or in conjunction with surgery. However a large number of cancers are inherently unresponsive to certain chemotherapy protocols. In some instances, chemotherapy works initially, leading to a reduction in tumour size, only to fail to produce a response when used again. The presence or emergence of drug resistance is responsible for the failure of chemotherapy and severely limits treatment options. Resistance in cancer involves a number of factors often acting in combination and we have focussed on a highly prevalent form of drug resistance in cancer. This resistance pathway involves the use of a pump at the surface of cancer cells which prevents accumulation of drugs within the cells, thereby circumventing their actions. A great deal of effort has centred on the discovery of drugs to block this pump and restore the effectiveness of chemotherapy. To date, there are no such compounds available for clinical use. Our proposal aims to provide detailed information on how this pump recognises drugs and ejects them from cells. By providing this information it will be possible to design new inhibitors of the protein or modified anti-cancer drugs to evade its influence.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: in vivo significance of Wnt loading on exosomes.
Funder: Wellcome Trust

Abstract: During development and tissue maintenance, cells acquire different characteristics so they can contribute to structures that are appropriate to their location. Much of this positional information relies on chemical signals that are produced by other cells. Some of these signals, called morphogens, spread over many cell diameters and form a concentration gradient that other cells use to compute their position. Examples of morphogens include the secreted proteins called Wnts, which are found in most animals, including humans and flies. These proteins are of great interest, not only because of their roles during development and stem cell maintenance but also because their misregulation often leads to cancer. Wnt proteins are tightly associated with cell membranes because they carry two lipids. Hence they must be packaged in such a way that they can be released from producing cells and spread in the extracellular space. We have found that a fly Wnt is present on small membrane vesicles c alled exosomes. We suggest that these structures carry Wnts within tissues. We propose to analyse the composition of exosomes and to devise ways to inhibit their formation so that their role in Wnt transport can be assessed.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulation of microtubule nucleation by Mto1/2 complex and the gamma-tubulin complex.
Funder: Wellcome Trust

Abstract: All living cells, from simple yeasts to humans, contain small microscopic fibers called microtubules , which can be used for a wide variety of cellular functions. The most universal function for microtubules is to mediate the separation of chromosomes during cell division, and drugs that alter microtubules are important, for example, in treating cancer. However, microtubules also have diverse important functions in non-dividing cells, such as serving as tracks upon which various components are transported inside cells. Microtubules can also be organized in different ways to help support specialized, cell-specific shapes in different cell-types in the body, such as nerve cells and muscle cells. Many inherited human disorders, especially relating to brain development, affect the structure or behavior of microtubules. In a test tube, microtubules can be created in a spatially random fashion. However, inside cells, the formation of microtubules is very tightly controlled in both space and time. Our proposed research aims to study the machinery regulating the formation of microtubules. We will use simple yeast to study these problems, because the basic mechanisms are similar to human cells but easier to manipulate experimentally.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural studies of heterochromatin protein 1 (HP1) interaction with chromatin .
Funder: Wellcome Trust

Abstract: Our genetic information is encoded in DNA. In the cell nucleus DNA is packaged by wrapping around clusters of proteins (histones), in a complex called chromatin, which has the appearance of a string of beads (each bead is a nucleosome). This can be coiled up to package the nucleosomes (and DNA) further. When the nucleosomes are tightly packaged the chromatin is said to be closed and the information in the genes is inaccessible; conversely, if they are loosely packed the chromatin is open and the genes become active. Whether chromatin is open or closed depends partly on non-histone proteins. We will study one such protein, HP1 (heterochromatin protein 1). It plays several important roles in the cell nucleus: maintaining the integrity of chromosomes, regulating some genes, and participating in DNA repair. Defects in HP1 can lead to disease, including cancer. In order to have a chance of intervening in aberrant processes we need to understand how HP1 plays its role in stabilising closed chromatin. We will use various approaches to understand the interactions between isolated components of the chromatin and HP1. We aim to learn how HP1 contributes to the closed state of chromatin and inactivates genes located there.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Clinical PhD Programme at the University of Cambridge: 'Functional characterisation of responses to DNA damage in human cells.'
Funder: Wellcome Trust

Abstract: Failure of accurate DNA damage sensing and repairing mechanisms manifest as a variety of human diseases including cancer. Cytotoxic chemotherapy and radiotherapy remain the most beneficial in terms of cancer treatments and largely act through the generation of DNA damage. Accuracy and efficiency of DNA damage detection and repair requires the recruitment and subsequent post-translational modification of various proteins. Ubiquitylation and sumoylation are highly dynamic and reversible enzymatic processes that play crucial roles during the execution of DNA damage sensing and repair. Further characterization of the enzymes involved in these processes is required in order to fully understand how the DNA damage response (DDR) is regulated and has the potential to provide new therapeutic targets. PIAS SUMO E3 ligase enzymes are necessary for human cells to respond appropriately to and effectively repair DNA double-strand breaks. ZIMP7 and ZIMP10 are two PIAS -like proteins that also contain a SP-RING/Miz zinc finger domain that potentially confers E3 ligase activity. Very little previous research has been focused on these proteins. I have demonstrated that both ZIMP7 and ZIMP10 are recruited to sites of DNA damage induced by laser micro-irradiation in cultured human cell lines. My goal now is to characterize the precise functions of ZIMP7 and ZIMP10 in the DDR.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms for Remodelling Chromatin.
Funder: Wellcome Trust

Abstract: The genes of most complex organisms such as plants animals and ourselves exist as a compact structure called chromatin. Chromatin must be unfolded for genes to be turned on and, conversely, it is often condensed to help prevent certain genes being active at the wrong time or place. All complex organisms use a combination of different strategies to change the structure of chromatin. One of these strategies involves the use of a family of motor proteins known as Snf2-related proteins. We will in vestigate the biomechanics of how these Snf2-related motors work. One of our major aims is to improve the understanding of the structure of these motors and to build a picture of how they interact with chromatin. Using bakers yeast as a model organism we will also investigate at which genes these motors act, how long they remain present at these genes and what changes they make to chromatin structure while they are there. This information will help us to understand how genes are regulated. This is of fundamental importance to many biological processes and may provide insight into what underlies the misregulation of genes in human diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Unfolding the Papers: Opening up UCL's Historic Material in the Field of Genetics
Funder: Wellcome Trust

Abstract: Objectives This proposal for a Research Resources in Medical History award represents Phase 1 of a two-stage project to catalogue, preserve/conserve and digitise UCL's important genetics collections. The main objectives of Phase 1 are to undertake essential cataloguing, preservation, conservation, and survey work in preparation for digitisation. Should Phase 1 be funded by Research Resources in Medical History, further funding will be sought from other sources to undertake the digitisation work in Phase 2. The collections at the heart of this proposal are as follows: The Papers and Fingerprint Collection of Sir Francis Galton. Other related genetics collections, namely the papers of statistician and eugenicist Karl Pearson, geneticist John Burdon Sanderson Haldane, physician Lionel Sharples Penrose, statistician Egon Sharpe Pearson and British statistician and geneticist Cedric Austen Bardell Smith, embryologist Sir Gavin De Beer and statistician and author of works on heredity Arthur Dukinfield Darbishire. Deliverables " Creation of a total of approximately 24,270 catalogue records below series level, comprising: o ca. 4,670 from the Galton Collections o ca. 19,600 from the related genetics collections " Essential conservation and preservation " A detailed survey of the material to assess and report on its suitability for digitisation on the basis of technical, IPR, and ethical considerations, identifying all issues likely to affect the cost and quality of the digital images to be produced in Phase 2.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Developmental programming of stress responses in Indian children and their association with cardiovascular risk and cognitive function.
Funder: Wellcome Trust

Abstract: Recent research suggests that the association between lower birthweight and higher rates of diabetes and heart disease can be explained by an increased sensitivity to stress. This leads to raised stress hormones and, in turn, increased cardiovascular risk factors such as high blood pressure and insulin resistance. I will look for evidence for this in 250 children aged 13-14 years in Mysore, India, who are a part of an ongoing study since birth. I will take baseline measurements of indicators of stress, which include hormone levels (salivary cortisol), blood pressure and heart rate. I will induce stress in the children using a commonly recommended, humane method, and measure changes in the above indicators. Since stress can also influence brain function, I will also assess their memory and other aspects of intellectual function, using locally developed tests. This study will show whether low birthweight could increase the risk of adult disease through increased stress-responsiveness.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: GENERIC HEALTH RELEVANCE
Title: Multidisciplinary studies of protein folding, misfolding and assembly.
Funder: Wellcome Trust

Abstract: Proteins are linear strings of amino acids that fold into defined three-dimensional structures. The sequence of the amino acids specifies the energy landscape, which determines the protein s structure, pathway of folding and function. Our goal is to investigate these energy landscapes and understand the effects of factors that might modulate them. Alterations in sequence or solution conditions, for instance, might promote misfolding or aggregation. Central to our approach is investigation and c omparison of families of proteins: How are they the same and why are they different? (1) We will use model proteins to determine the importance of structural complexity and sequence in defining energy landscapes. How do mutations that change the sequence affect the folding? (2) Most proteins have more than one folded module (domain). Thus, domains do not exist in isolation. How are proteins affected by their neighbours? How have they evolved to avoid misfolding? Do pathogenic mutations cause misfolding? (3) It has recently become apparent that a significant proportion of signalling proteins have large disordered segments, which fold upon binding to a target. We will use the tools developed to study globular protein folding to investigate the folding upon binding of these intrinsically disordered proteins.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Training Programme in Translational Medicine and Therapeutics at the University of Cambridge.
Funder: Wellcome Trust

Abstract: Background and key goals: DNA damage and DNA secondary structures such as G quadruplex DNA (G4 DNA) pose obstacles to DNA replication. There has been much recent interest in stabilisation of G4 DNA structures as a potential therapeutic strategy for killing cancer cells (1). Refinement of such approaches however require an understanding of the mechanisms by which G4 DNA is replicated and the consequences of defects in its replication. Key players in enabling G4 DNA replication are specialised DNA helicases that are able to unwind G4 DNA (2,3). Recent data has also implicated a number of specialised DNA polymerases, normally involved in translesion synthesis across damaged DNA, in G4 replication (4,5). Crucially, defective replication of G4 DNA caused by loss of one of the TLS polymerases, REV1, results in deregulated gene expression caused by failure to propagate epigenetic histone marks from one cell generation to the next (6). My main goals are to study the role of G4-unwinding DNA helicases in maintaining epigenetic stability, to understand how they interact with translesion synthesis in damaged and G4 DNA replication and to explore the implications of the phenomenon of G4-induced epigenetic instability for cancer, ageing and for G4 DNA as a therapeutic target.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Genomic imprinting and the epigenetic control of genome function.
Funder: Wellcome Trust

Abstract: Now that we know the sequence of our DNA which represents the code for all the proteins in our cells, it is important to understand how the DNA functions to encode these proteins. All our cells carry the same DNA that must be packaged into a DNA-protein structure called chromatin. The packaging of DNA into chromatin is a highly regulated process and is subtly different between different cells influencing, for example, how liver cells make liver proteins and muscle cells make muscle proteins. Som e parts of chromatin contain tightly packaged DNA and other parts, more loosely packaged DNA. Chemical flags called epigenetic marks are found on the DNA and associated proteins and influence the packaging of chromatin. We are interested in understanding how epigenetic marks are established and maintained and the extent to which they influence chromatin structure and function. This is not only important for understanding DNA regulation, but also it is important for understanding diseases such a s cancer and the normal aging process in which the normal chromatin becomes perturbed.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE