NIHRDataInsights/HRCSData huggingface dataset:
Title: Determining the mechanisms regulating immune-directed clearance of senescent cells to promote healthy ageing
Funder: Wellcome Trust

Abstract: The number of people over the age of 65 is predicted to double by 2060, accompanied by an increase in chronic diseases, which already consume up to 80% of healthcare costs. Developing therapies for chronic ageing diseases is, therefore, an urgent priority. A key driver of ageing diseases is telomere dysfunction and consequent cell senescence. Genetic ablation of senescent cells ameliorates diseases of ageing in mice, highlighting senescence as a promising therapeutic target. The immune system clears senescent cells, but with ageing, senescent cells accumulate causing disease. The mechanisms regulating senescent cell clearance in telomere-dependent ageing in vivo are unknown. I will test the hypothesis that senescent cells are not cleared with ageing due to telomerase-dependent dysfunction of the immune system. I will use the premature ageing telomerase mutant zebrafish I developed, which age in a telomere- dependent manner, and are exceptionally amenable for imaging and genetic manipulation. I will determine which leukocytes clear senescent cells in aged tissues in vivo, identify the key mechanisms involved and determine how these change with ageing. I will then test whether manipulation of these targets is sufficient to prevent or delay tissue degeneration and frailty in old zebrafish.

Lay abstract: As we age, we develop chronic diseases, which diminish our quality of life. Because the number of people over the age of 65 is set to double over the next 50 years, we urgently need to develop effective therapies to improve health and prevent chronic illness in the aged. A major medical problem associated with ageing is that the different tissues in our bodies become damaged over time. A major reason for this is the accumulation of old or “senescent” cells. It is likely that, as we age, our immune system becomes defective in its ability to clear senescent cells from tissues – if we could understand this, we might be able to put it right. My work will determine which immune cells are responsible for clearing senescent cells and whether they are impaired with ageing. Importantly, I will determine the reasons behind this and devise a strategy to promote the clearance of senescent cells in aged, damaged tissues. The ultimate aim of my work is to discover new ways to stimulate our natural immune system to clear senescent cells, promoting a healthy long life.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM
Title: Rhomboid-like proteins: from molecular principles to pathophysiological significance
Funder: Wellcome Trust

Abstract: The goal of this proposal is to transform our understanding of both the molecular mechanisms and the pathophysiological roles of members of the rhomboid-like superfamily. At the mechanistic level, our long-term research into this group of polytopic membrane proteins has led us to the hypothesis that the core function of the rhomboid-like domain is specific TMD recognition of substrates (of the rhomboid intramembrane serine proteases) and clients (of the non-protease members of the clan). Using a structural and biochemical approach, we seek to understand the molecular details of how this specific recognition is achieved. Biologically, rhomboid-like proteins have many functions, but we still have little understanding of their role in mammals, particularly of the rhomboid proteases. Building on our mechanistic aims, we plan to break this log-jam by pioneering systematic methods of substrate identification. We already know that iRhoms, catalytically inactive homologues of rhomboids, regulate inflammation, growth factor signalling and, as we have recently discovered, tumour growth. We plan to further elucidate these roles, both at the level of fundamental cell biology but also with a goal to reveal their potential medical significance. By the end of this work we expect to know which rhomboid-like proteins are useful therapeutic targets.

Lay abstract: Cells are the fundamental unit which form all organisms. They are responsible for how animals work, and their malfunction underlies almost all human disease. Our overall goal is to understand the molecular details of how cells communicate with each other, and how this signalling controls their behaviour. We focus on the rhomboid-like family of proteins, which we discovered. Our discovery was important because these proteins are present in all organisms. Since then we have researched how they work and their biological role in cell communication – both as a basic biological problem but also because there is good evidence that they are relevant to a wide range of human diseases. In this proposal we aim to answer questions about both their fundamental biology and their medical relevance, with a particular goal of transforming our understanding of rhomboid-like proteins in mammals, including humans.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM
Title: Mechanisms and consequences of T cell antigen receptor signalling for normal immune homeostasis and the development of autoimmune disease
Funder: Wellcome Trust

Abstract: T cells are essential components of the adaptive immune response and prime drivers of autoimmune diseases, yet we lack in depth understand of how responses are initiated and terminated, and even less understanding of the precipitating events that result in disease. Activation and termination of immune responses are balanced through cross-talk between tyrosine kinases and phosphatases immediately downstream of the T cell receptor. We will use genetically altered (GA) mice to manipulate early signals and address the contributions of the Src-family kinases, Lck and Fyn, and the phosphatase, PTPN22, to normal and abnormal activation of T cells. Genome wide association studies have identified PTPN22 as a major autoimmune susceptibility allele and its regulation of the Src-family kinases, amongst other substrates, influences T cell homeostasis. We will perform in vivo studies to follow the behavior of T cell populations from GA mice following antigenic challenge and underpin these with in vitro studies of the biochemical and biological processes that regulate T cell activation. Together these investigations will interrogate the contributions of: abnormal activation of T cells, cell intrinsic failures to terminate a normal response, and the failure to externally regulate a normal response, as drivers of autoimmunity.

Lay abstract: The major cause of autoimmunity is when a type of white blood cell, called a T cell, makes an immune response against one or more organs or tissues in the body. T cells are very important for mounting immune responses that protect us against pathogens, such as bacteria and viruses, and there are a number of failsafe mechanisms that generally prevent them from responding to self-tissues. Some people carry mutations in genes that put them at higher risk of developing autoimmunity. A number of these genes influence how T cells behave and these mutations increase the likelihood that T cells may attack self-tissues. Our research is focused on trying to understand how and why these genetic mutations alter the behavior of T cells. We will identify biochemical processes and pathways that become disregulated by these mutations. The primary aim of our research is to pinpoint pathways that go wrong so that we can use this information to develop therapies that may be used to alleviate disease.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM
Title: Cambridge Institute for Medical Research (CIMR).
Funder: Wellcome Trust

Abstract: A major objective for CIMR over the next 5 years is to better understand protein localisation, function and metabolism in a range of diseases in which genetic studies have identified the causative genes. Underpinning our core facilities is essential to achieve this objective and will provide added value to the considerable investment that the Wellcome Trust is already making to our scientific activities. Our present scientific goals are: (i) determination of the molecular mechanisms of intracellular protein aggregate formation and breakdown in health and disease, including the identification of novel therapeutic targets for protein conformational diseases; (ii) identifying and characterising the molecular machinery of intracellular membrane traffic and determining how traffic pathways are coordinated, regulated and modified in health and disease; (iii) the identification of genes, proteins and pathways increasing susceptibility to, or protection from, autoimmune diseases; (iv) determining the transcriptional regulation of haematopoietic stem cells. Our proposal includes funding of core specialist scientific staff, annual research retreats, funds to encourage young clinicians back into research and a case for 2 PhD students per annum. We aim to make CIMR a flagship in the UK for interdisciplinary research at the interface between clinical and basic research.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM
Title: Genetic analysis of post-developmental Rho GTPase signaling: identification and characterization of Rho signaling pathways required during the C. elegans immune response.
Funder: Wellcome Trust

Abstract: Cells respond to changes in their environment by altering basic properties such as their size and shape. They do this by activating proteins in an ordered sequence known as a signal transduction pathway. Many diseases arise from defects in these pathways and so identifying them and defining how they interact with each other is essential in understanding how normal cells function and in turn how mis-regulation leads to disease. Signal transduction pathways involving a gene known as Rho regulate many cellular properties and altered signaling through Rho pathways is associated with several diseases including cancer. Because the genes involved in signal transduction (including Rho) are similar in many animals we can study their functions using organisms that can be manipulated experimentally; such as the nematode C. elegans. Using C. elegans my research focuses on how Rho signaling pathways change cell shape and size following infection. The goal of this research is to identify new com ponents of Rho signaling pathways and how these pathways interact with others. Further analysis of these new pathways will contribute to our understanding of Rho s role in diseases and may lead to the development of drugs that target these pathways.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of leukocyte-stromal cell interactions in the pathogenesis of salivary gland inflammation and Sjogren's Syndrome.
Funder: Wellcome Trust

Abstract: Treatments aimed at blocking white cell activation during inflammation have proved to be limited in their effectiveness: it may be that we are hitting the wrong target. Stromal cells give tissues their structure, performing maintenance jobs to keep the cells within the tissues in good order. However, stromal cells are more than just caretakers, they act like sensitive burglar alarms, alerting the emergency services of the body, the white blood cells, to converge on the target tissue and eliminat e dangerous intruders. However, in some forms of inflammation and cancer these cells become transformed and continuously sound the alarm by producing inflammatory messengers and survival factors for the white cells that are then continuously attracted to and proliferate aberrantly in the tissue. The aim of this project is to determine the factors that stimulate stromal cells to be so aberrantly activated within the salivary glands in a condition called Sjogren s syndrome. This is a common rhe umatic disease, in which the local inflammation becomes so severe and persistent that some patient develop cancer. We hope that our findings will lead to the development of new diagnostic tests and treatments for this disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM
Title: Antibody conjugates via disulfide bridging; towards therapeutic and diagnostic applications
Funder: Wellcome Trust

Abstract: Previous research has demonstrated that dihalo- and dithio-maleimides offer a powerful approach to the selective, rapid, quantitative, and reversible modification of a disulfide bond in a peptide (19b-d). Early studies have revealed that these maleimide constructs can also be used to bridge the disulfide bond in the anti-CEA scFv antibody fragment with maintained activity. This project will involve the design and synthesis of optimised 3,4-substituted maleimide reagents to enable the efficient bioconjugation of antibodies, with a focus on applying this technology to the construction of antibody-enzyme conjugates for ADEPT and ELISAS.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM
Title: The mechanism of linear ubiquitin chain formation:structural and functional investigation of LUBAC, a novel regulator of immune signalling.
Funder: Wellcome Trust

Abstract: Cells use a variety of mechanisms for communication, one of which is the attachment of a small protein called ubiquitin to another protein. This process is called ubiquitination and has profound consequences for the fate of the protein being modified. Ubiquitin molecules can be stitched together into chains. Depending on how they are linked this has different effects on the protein they are attached to: some types of chains induce destruction of the protein, while others send a signal to activat e an immune response. We are interested in understanding how a newly identified type of chain that is a regulator of immunity and inflammatory responses is produced by an enzyme called LUBAC. Specifically, we would like to determine the three-dimensional structure of this enzyme to understand on a molecular level how it is able to produce specific ubiquitin chains and attach them to a protein called NEMO. NEMO is part of a protein complex that, if mis-regulated, can induce inflammation and auto -immune disease. Hence a detailed knowledge of the molecular mechanisms that regulate its function could help to better understand the cause of disease and point towards new types of drugs against inflammatory disorders and auto-immune disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM
Title: Understanding the structure and mechanism of macromolecular machines that regulate chromatin dynamics.
Funder: Wellcome Trust

Abstract: The genetic material in higher organisms is wrapped around proteins called histones to form nucleosomes, which are then arranged to form chromatin. Nucleosomes protect and stabilise the DNA and also allow a large amount of genetic material to be packed into a relatively small space. However, proteins need to access DNA to repair it when it becomes damaged. This is important to prevent mutations which can lead to cancer and other diseases. Specialized protein complexes are able to recognise the damage, label it in different ways to initiate repair, exchange histone components for others, drive nucleosomes along the DNA to expose the damage and allow access by repair enzymes, and finally to clear up the mess after the DNA is repaired to restore the chromatin to its original state. I am proposing to investigate how several interconnected protein machines carry out these complex tasks by using high resolution structural techniques to look at the shapes, interactions and conformational cha nges of the complexes involved in different stages of the repair process. I will complement these analyses with biochemical studies to reveal the molecular details of the workings of these machines in DNA repair.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM
Title: Regulatory and effector B cell function in childhood rheumatic disease.
Funder: Wellcome Trust

Abstract: Many chronic diseases in humans are autoimmune conditions, which result from the immune system attacking the body. Recent studies have identified a new set of white blood cells, called regulatory B cells which may provide a natural antidote to this problem. Our pilot results suggest that these cells may not work properly in a severe childhood autoimmune condition called Juvenile Dermatomyositis (JDM) which causes muscle weakness, skin rashes and significant disability. This project aims to 1) Identify better markers for regulatory B cells, so we can detect and study their role in patients. 2) Discover the cell machinery that allows these cells to control the immune system. 3) Ask if the extent of cell defects correlates with the severity of disease in JDM. 4) Find out why the cell machinery goes wrong. Ultimately the goal of this research project is to gain a better understanding of how the immune system can be regulated and apply this knowledge to improve the treatments of patients with JDM.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM
Title: Jointly modelling phenotype and function in the fine-mapping and follow-up of disease associated loci.
Funder: Wellcome Trust

Abstract: In recent years we have discovered many parts of the genome that vary from person to person, with different forms conferring different risks of developing a disease. Sometimes the same part of the genome is found to change the risk of many related diseases, or affect both disease risk and another trait, or even be associated with changes within the cell itself. We would like to be able to combine information across studies of these different diseases and traits, to learn how these traits relate to each other, and how the differences in our genomes contribute to disease risk. The best statistical method for combining such datasets is still unknown, and applying an inappropriate method could lead to false conclusions. My project will develop the mathematical underpinning required for such analyses and turn it into algorithms and software that other researchers can freely use. I will then apply these techniques to real data, including a large collection of genetic data on various disea ses related to defects in the immune system. Finally, this project will investigate how to use these analyses to develop specific hypotheses about disease biology, and how to use new experimental techniques to test and refine these hypotheses.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM
Title: How the strength ofT cell receptor signalling controls cytotoxic T cell polarisation for targeted killing
Funder: Wellcome Trust

Abstract: The proposed project aims to investigate how cytotoxic T lymphocytes (CTL) respond to variations of T Cell Receptor (TCR) signal strength at an intracellular level.Altered peptide ligands (APL) have been characterised to change the TCR: peptide-major histocompatibility complex interaction and subsequently alter TCR signal strength. Using APL provided by Ed Palmer, his biophysical measurements of these interactions, particularly dwelltime, can be correlated to physiological measurements. These will aim to identify any killing defects imposed by the APL and consequently any intracellular causes of defects will be investigated. This includes investigating strength of TCR signalling modules, such as calcium flux and extracellular signal-related kinase phosphorylation. The project will progress to investigating defects in conjugation and organisation of the immune synapse by immunofluorescence techniques. Next, defects in centrosome and granule polarisation will be investigated via live cell imaging to identify variations in velocity, granule clustering dynamics and timing post signalling and synapse formation, in order to elucidate how the order of these events are impacted by dwell time. This will provide insights into the determinate stages for target killing. Further work will involve following organelles with roles in TCR signalling but poorly defined roles in CTL killing, such as recycling endosomes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM
Title: High-throughput identification of genes which regulate ROS and DNA damage response in senescence and their effect on hematopoietic stem cells
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Cellular senescence is defined by irreversible loss of division potential of somatic cells and has been classically characterised in vitro as the result of a DNA damage response (Ddr) to uncapped telomeres. Senescence is a tumour suppressor and contributes to age-dependent tissue function decline. I recently found that production of Reactive Oxygen (ROS) is a result of Ddr and part of a positive feed-back loop that maintains and stabilises senescence. By combining in-silico analysis and sequential inhibition of pathway intermediates, I identified a signalling pathway connecting Ddr with ROS involving MAPK14 and TGFB2 and proved that increased ROS levels maintain senescence by stabilising Ddr. To comprehensively identify the whole signalling network that maintains senescence, I propose a large-scale screen of genes involved in ROS and Ddr following IR-induced senescence, using a siRNA library. Library and cell handling will be automated using robotic stations. ROS and Ddr will be analysed using high-content automated imaging systems Analysis of the ROS-regulatory pathways will be carried out by a combination of integrated network approaches, mechanistic stochastic models and pathway sequential inhibition. Secondly, I will determine the impact of genes identified in the in vitro screen on stem cell function in vivo. For that, I will use G3mTERC-/- mice. Age-dependent telomere dysfunction has been shown to limit the repopulation capacity of Hematopoietic Stem Cells (HSCs). To determine the effect of the newly found genes on stem cell function I will infect HSCs from mTERC-/- mice with specific shRNAs and inject them into recipient mice. This will allow me to study the effect of specific genes on HSC maintenance and differentiation by analysing their ability to rescue mTERC-/- dependent defects in HSC repopulation. Newly identified genes might represent targets for therapies aiming to improve regeneration and organ maintenance and might have an impact on ageing.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM;BLOOD