NIHRDataInsights/HRCSData huggingface dataset:
Title: Mechanisms and consequences of HIV 1 effects on phagocytosis and autophagy in macrophages.
Funder: Wellcome Trust

Abstract: People infected with human immunodefiency virus (HIV)-1 develop weaknesses in their immune system that makes them more prone to other infections. In order to develop a better understanding of how the virus does this, I aim to study the effects of HIV-1 infection of macrophages that are key cells in the body s immune system. Others have previously shown that HIV-1 affects two important macrophage functions, phagocytosis and autophagy, that function to take up microbes and degrade them within the cell. I aim to increase our understanding of the effects of HIV-1 on these processes by defining the way in which the virus causes its effects and the consequences for the immune system, particularly in the defence against tuberculosis that remains a significant problem for HIV-1 infected people. I will conduct my experiments in laboratory cells that resemble macrophages and macrophages obtained from people, to help ensure that my findings are representative of the effects of the virus within pa tients. The findings of this project will influence future research and may inform future development of treatments for HIV-1 infected patients.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Ribosomal frameshifting and readthrough in virus gene expression.
Funder: Wellcome Trust

Abstract: Cellular protein synthesis is performed by the ribosome. Once a gene is copied into messenger RNA (mRNA), the ribosome binds and moves along it in three-base (triplet) steps, adding one amino acid per step to the growing protein chain until a stop signal is reached (stop codon) when the completed protein is released. The genetic material of many viruses (the genome) is tiny in comparison to their host so they have evolved ways to increase their protein coding capacity. In ribosomal frameshifting and readthrough, signals in viral mRNAs cause the ribosome to behave differently, either by reading a different set of triplets (frameshifting), or by failing to recognise stop codons efficiently (readthrough). Frameshifting and readthrough permit viruses to synthesize longer proteins essential to the virus life-cycle. I will investigate how perturbing frameshifting or readthrough affects the virus. I will do this by changing the sequence of the virus s genetic material or by growing the virus in cells that have been treated with agents that affect frameshifting/readthrough. I will also examine how readthrough signals lower the efficiency with which stop codons are recognised by the ribosome. Together, these studies will determine whether these translation strategies are good targets for antiviral therapy.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Discovery and Development of Drug Candidates for Neglected Diseases.
Funder: Wellcome Trust

Abstract: The parasitic diseases, Leishmaniasis, African sleeping sickness and Chagas' disease, annually cause over 120,000 deaths world-wide. Despite this terrible death toll, the available drugs are generally not fit for purpose, suffering from multiple issues, such as lack of efficacy and unacceptable levels of toxicity, including death. Despite encouraging developments, significant gaps are still impeding the discovery of new treatments for these diseases. These include a general lack of validated targets, drug discovery effort, and insufficient hits and leads to counteract the normal attrition of drug discovery. We will address these gaps through a unique alliance between the university based Drug Discovery Unit and the major pharmaceutical company Pfizer. The consortium brings together Dundee's world renowned parasitology and extensive experience developing hits and leads for neglected diseases, and Pfizer's substantial later stage discovery and development expertise and infrastructure. Pfizer's extensive target-based knowledge and chemical matter will substantially strengthen our ability to sustain a portfolio of antiparasitic projects, through to the delivery of clinical development candidates with our established partner, DNDi. Science 10 Our goal is to deliver at least one credible pre-clinical candidate, together with a pipeline of hits and leads for one or more of these diseases within the 5 year programme.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: A glycosomal signalling pathway regulating trypanosome development.
Funder: Wellcome Trust

Abstract: African trypanosomes are responsible for human sleeping-sickness and the cattle disease, nagana. These diseases represent a major restriction on health and economic well-being in sub-Saharan Africa. When the parasite is transmitted to its vector, tsetse flies, it requires to detect its new environment. This sensing mechanism is dependent upon the metabolites citrate/cis aconitate and reduced ambient temperature. This signal is transduced into the cell via recently-identifed surface proteins exp ressed only on the parasite s transmissible stumpy-form . Thereafter, an inhibitory signalling molecule (a so-called tyrosine phosphatase) is inactivated and differentiation begins. In recent work we have discovered that the target of this inhibitory molecule is another signalling protein, in this case one that stimulates differentiation. Interestingly, this protein is trafficked to unique metabolic organelles in the parasite called glycosomes. Glycosomes control parasite metabolism as well as several other biosynthetic processes; their enzymatic composition is also stage-regulated. Here, we will investigate the first steps in the signalling-cascade, the distribution of the signal to different glycosomal-subsets during differentiation and the functional targets within this unusual organelle. Our experiments will construct a joined-up picture of parasite environmental-sensing and provide new information on glycosome biology and control relevant to related organelles in humans and o ther animals.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Proteases as next generation therapeutics for Influenza A.
Funder: Wellcome Trust

Abstract: Each year 3-4,000 deaths are attributed to influenza in the UK alone and 250-500,000 world wide. During pandemic outbreaks, the death toll shoots to a high number. For instance, 20-50 millions deaths are estimated to have resulted from 1918-flu outbreak. Even the recent outbreak of swine-flu, although fortunately did not cause significant casualties as predicted, created a pandemic alert. In order to tackle such outbreaks, we need to have drugs that would disable the virus'es ability to penetra te human receptors, prevent its integration within human genes and most importantly disrupt its ability to be contagious. My research will be focused on developing therapeutic drugs with above mentioned functions.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Molecular mechanisms of gating ion channels and transporters in bacterial homeostasis.
Funder: Wellcome Trust

Abstract: Antibiotics have enabled clinicians to control infections and have influenced the development of modern medicine from transplant surgery to cancer chemotherapy. Recently, this progress has been threatened by two developments, the rise in multi-antibiotic resistant strains in the hospital setting and a dramatic reduction in the rate of development of new antibiotics. Solutions to these problems will come from many sources. Our team is seeking solutions from research on channels and transporter s that protect bacteria from sudden changes in the environment. Channels control the movement of small molecules and ions across the membrane that surrounds the cell. The systems we study are present in almost all bacterial pathogens, but are absent from man. This makes them good targets for novel antimicrobial therapies. Our team combines skills from several different fields including biochemistry, microbiology, physics and chemistry, which will enable rapid advances to be made. By understandi ng how these channels work we can design new molecules that will be the forerunners of the drugs needed to treat antibiotic-resistant bacteria. Exploiting our knowledge will provide new tools for the clinician.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: In vivo imaging of Trypanosoma cruzi infections as a tool for assessing drug efficacy against chronic Chagas disease.
Funder: Wellcome Trust

Abstract: Chagas disease is caused by infection with the American trypanosome, Trypanosoma cruzi, and is a major public health problem throughout Latin America. The disease causes an enormous amount of human suffering and acts as a block on development in one of the poorest regions of the world. There are no vaccines against this insect-transmitted single-cell parasite and current drugs are unsatisfactory for reasons that include toxicity and limited efficacy. The development of new treatments for this g reat neglected disease has been categorised as a research priority by the World Health Organisation. Most of the serious health problems that affect individuals infected with T. cruzi, are restricted to those who develop the chronic stage of the disease; about 30% of the total. In this project, we seek to exploit recent developments in non-invasive imaging technology to provide new ways of understanding chronic Chagas disease. Questions of major importance that we will address include: (i) C an we develop an experimental system for rapidly assessing new drugs? (ii) Is it possible to cure chronic Chagas disease? (iii) Why is there such a wide spectrum of symptoms in those infected with T. cruzi? (iv) Is there a relationship between disease severity and parasite strain?


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Isolation and characterisation of lytic bacteriophages which infect Burkholderia pseudomallei.
Funder: Wellcome Trust

Abstract: The tropical bacterial pathogen Burkholderia pseudomallei causes a serious disease called melioidosis, which can be manifested in a range of symptoms including severe skin infections and pneumonia. Existing antibiotics are not very effective in treating melioidosis. It is also difficult to diagnose the presence of B. pseudomallei and to genetically manipulate it for scientific purposes. Like all bacteria, B. pseudomallei has natural enemies. One of these enemies are viruses known as bacteri ophages. Bacteriophages are able to specifically destroy particular species of bacteria, and because of that they are sometimes used to treat certain bacterial infections in a treatment called phage therapy. They can also be used as tools to detect or manipulate specific bacteria. Surprisingly, no bacteriophages capable of destroying B. pseudomallei had previously been identified. This stimulated us to initiate this work. In a pilot project we have demonstrated that B. pseudomallei-specific bacteriophages could be isolated from the environment in Thailand. In the proposed research programme we will isolate several B. pseudomallei-specific phages and study them in great detail. This will allow us to identify phages which are the most promising for exploitation.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Acceleration of the Development of Vaccines and Diagnostics for Typhoid Fever using a human challenge model.
Funder: Wellcome Trust

Abstract: Typhoid is a serious infection which kills up to 600,000 people every year. Many children and adults are affected by the disease and it is the commonest bacterial cause of fever in children attending hospital in some parts of South Asia. It is very expensive to undertake the field studies that are needed to see if new vaccines work and this has stalled development of some new generation vaccines which might give better protection against typhoid. In this project we will deliberately infect healthy volunteers with the germ that causes typhoid and once we have established a reliable model of infection, we will test a new vaccine made by Emergent Biosolutions to see if it can prevent the volunteers developing infection. We hope that these studies will give us confidence in the vaccine so that it can be moved forward to field trials and eventually save lives by its use. We will also use the model to understand typhoid infection better and study which components of immunity are important in vaccine protection. Finally, we will use the model to try to develop new blood or urine tests for diagnosis of typhoid to improve the diagnosis of this disease.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: The detection and management of ivermectin resistance in human onchocerciasis.
Funder: Wellcome Trust

Abstract: An increasing number of control programmes are delivering safe and affordable drugs against tropical parasitic diseases such as River Blindness, treating regularly as many people as possible for as long as necessary to bring long-lasting benefits to afflicted communities. There is a chance that some parasites may develop drug resistance (http://news.bbc.co.uk/2/hi/health/6753003.stm). Some treated parasites are genetically different from untreated ones, suggesting that parasites may be adapting to treatment. This project will analyze parasitological data already collected in treated and untreated areas of Ghana and Cameroon and will link the types of response to treatment observed in people to the genetic types of parasites harboured by the same persons, and use this information to develop computer tools to investigate if drug resistance may threaten River Blindness control in Africa. These computer programs will simulate populations of parasites in people and in the flies that transmi t the infection enabling understanding and prediction of how resistant parasites may spread in human populations, and how this could be minimized to protect investments in parasite control. This will facilitate identification of drug resistance before it reaches high levels and will allow us to devise strategies to prevent it from becoming a major public health concern.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: A Biological Repository for Schistosomiasis Research.
Funder: Wellcome Trust

Abstract: Schistosomiasis is a parasitic disease affecting ~200 million people in developing countries, especially sub-Saharan Africa. At the Natural History Museum (NHM), London, there has been a long-term research effort to investigate this disease, its causative agent (a flatworm) and the snails that transmit the disease. The laboratories at NHM already maintain a living collection of the parasite and snails, and preserved research/reference material, acting as World Health Organization Collaborating Centre for the Identification and Characterization of Schistosomes and their Intermediate Snail Hosts. The applicants seek funding to expand this collection in partnership with a new initiative to understand the control and elimination of schistosomiasis. This initiative, known as SCORE, involves parters from around the world. By working with SCORE, NHM will acquire valuable parasite and snail samples that will be stored and made available to the global research community both now and in the future as new techniques of analysis emerge. SCORE s activities represent a unique opportunity to collect these samples, which may not arise in future. To be effective in this endeavour, funding is required to consolidate existing material into enhanced storage systems, combine this with material collected by SCORE and others, and enable access to the combined collection.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Association between malaria and non-typhoidal salmonella bacteraemia among African children. A proposal for a case-controlled study.
Funder: Wellcome Trust

Abstract: Studies have demonstrated that up to 12% of children with severe malaria are co-infected with bacteraemia associated with 2-4-fold increase in mortality. There appears to be a real association between malaria and NTS infections especially in young and anaemic children (1, 7, 11, 12, 13, 15, 16, 17, 18). However the mechanisms of this association are poorly understood and no published studies have included community-based comparisons that are needed to assess the strength of the association, the likely direction of the causal chain and risk factors for exposure. The only case-control study that I am aware of failed to identify the source of NTS infection in Kenyan children. (Kariuki et al, unpublished). From a public health perspective it is important to understand more about the association between malaria and NTS infection in order to design for rational interventions such as antibiotic use in high-risk children and community preventive strategies. I propose to conduct a case control study to Identify risk factors for NTS bacteraemia in children living in a malaria endemic area of Tanzania where the majority of blood borne infections isolated from hospitalised children in 2006-7 was due to NTS.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Human Monoclonal Antibody Therapy for Rhodesiense Sleeping Sickness.
Funder: Wellcome Trust

Abstract: Human African Trypanosomiasis (HAT) remains a serious health problem in Central Africa. Treatment of the disease has changed little in 40 years. Current drugs have severe side effects and there is a desperate need for new medicines. Fortunately, most trypanosomes cannot infect humans due to an innate immunity protein, called apoL-1, present in blood. The two types of human infective trypanosomes, one present in West Africa and one in East Africa, have evolved a mechanism to counteract this innat e immunity. In the East African form it has been demonstrated that expression of a single gene, known as SRA, is sufficient to confer human infectivity as the SRA protein binds to the human innate immunity protein apoL-1 and prevents it from killing the trypanosome. The objective of this application is to produce a new treatment for East African HAT by producing specific human monoclonal antibodies that bind SRA block the binding of apoL-1, in turn this would render the trypanosome susceptibl e to killing by apoL-1. The use of human antibodies for the treatment of disease is an emerging technology that has had recent success with drugs such as Herceptin and is characterized by little, or no, off-target side effects.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Mechanisms of drug resistance and immune evasion in African trypanosomes.
Funder: Wellcome Trust

Abstract: Drug resistance and immune evasion present major challenges when tackling diseases caused by the African trypanosome, Trypanosoma brucei. The diseases are fatal if untreated with effective immune evasion allowing persistence and drug resistance now widespread. We recently developed a genome-scale loss-of-function screening system and demonstrate unprecedented power in identifying the genes that underlie specific cellular processes in these organisms; the screening system is based on high-density RNA interference libraries. We have screened for genes involved in drug resistance and the gene silencing mechanism required for effective immune evasion. These screens identified genes encoding transporters for the uptake of four of the five drugs used against human trypanosomiasis; the fifth drug may enter the cell by diffusion and we identified a prodrug activation mechanism for this compound. We now propose further screens for deeper surveys and for the identification of more genes linked t o these processes. We then propose the subsequent functional characterisation of these genes and the proteins they encode. This novel screening approach promises major advances in our understanding of the mechanisms of drug resistance and immune evasion in these important pathogens and the findings will present new opportunities to develop improved interventions.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Key interactions in a tripartite multidrug efflux pump of pathogenic bacteria.
Funder: Wellcome Trust

Abstract: Bacterial diseases are a threat to humans and animals throughout the world, causing great suffering, death and economic cost. This is especially so as we see new disease-causing strains emerging, and old ones re-emerging as they become increasingly resistant to the antibiotics that have protected us for decades. It is therefore more important than ever to perform sophisticated studies on drug resistance, to learn how bacteria infect us and how they survive antibiotic treatment, and to find new w ays to combat them. In addition, understanding these fascinating life forms, which are relatively simple, experimentally tractable and genetically well characterized, allows us to mine a rich seam of knowledge about how all living cells work. In our laboratory we have established powerful experimental approaches to study the biology of pathogenic bacteria, in particular the machineries that bacteria build to expel a wide range of antibiotics from their cell, allowing them to become multidrug res istant. Our work will continue to increase understanding of the structure, assembly and operation of these remarkable bacterial machineries, and examine how they can be inhibited.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Mechanism of Action of Novel Inhibitors of the Bacterial RNA Polymerase.
Funder: Wellcome Trust

Abstract: Many activities that allow organisms to grow, remain alive and viable rely on molecules resembling small machines. In bacteria, the machine which is responsible for accessing information contained in the genes is the RNA-polymerase (RNAp). In order to access this information, the RNAp has to separate the two strands of the DNA molecule, which represents a gene, in a process collectively called transcription-initiation. Because the RNAp carries out an essential function necessary for the survival of the bacterial cell, the RNAp is an attractive target for drugs to treat bacterial infections. For instance, the widely used antibiotic rifampicin inhibits the RNAp. However, the frequent emergence of rifampicin-resistant harmful bacteria necessitates research into new compounds to combat bacterial infections by inhibiting the RNAp. We have recently identified two naturally-occurring small proteins, called Gp2 and P7, which inhibit the RNAp very effectively and have several of the desirable f eatures for potential development into novel drug-like compounds for inhibiting the RNAp. Here, we will study exactly how Gp2 and P7 bind to and inhibit the RNAp. Since Gp2 and P7 inhibit the RNAp at the level of transcription-initiation, our analyses will also extend our understanding of how the RNAp carries out transcription-initiation.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION