NIHRDataInsights/HRCSData huggingface dataset:
Title: Identification of rheumatoid arthritis causal genes using functional genomics
Funder: Wellcome Trust

Abstract: Genome-wide association studies (GWAS) have been used to great effect to identify genetic variants that predispose to rheumatoid arthritis (RA). 90% of associated variants are non-coding and thought to be involved in transcriptional regulation, but their functional role has been under explored. I will perform functional characterization of RA risk loci with the aim of translating GWAS findings into biological disease mechanisms and suggesting therapeutic targets. My key goals are: 1. To identify the genes that cause RA. I will identify chromatin interactions between RA loci and their targets using capture Hi-C in primary CD4+ T-cells and synovial fibroblasts from RA patients. I will explore whether associated SNP genotypes are correlated with differential expression of the genes they interact with. 2. To elucidate the mechanism by which RA-associated SNPs alter their target genes. Regulatory elements containing disease-associated SNPs will be identified in primary cells from patients and their functional importance will be verified using CRISPR/Cas9 genome editing. 3. To translate research findings into patient benefit. Identified causal genes and pathways will be intersected with known drug targets to identify existing drugs whose safety and efficacy has been proven in other diseases and which could potentially be re-purposed to treat RA.

Lay abstract: Rheumatoid Arthritis (RA) is a chronic disease that causes inflammation and pain in the joints. There is currently no cure and treatments are sometimes not effective. Genetic studies have identified changes in the DNA sequence that increase the likelihood of developing RA but so far it is not known how the DNA changes increase risk of RA. The aim of this project is to identify which genes the RA variants affect and to understand how changes in the DNA sequence between genes cause RA. It is thought that the DNA changes control the activity of genes but the genes being controlled may lie some distance away. However DNA is folded so that the changes that predispose to RA and the genes they regulate are brought together. These folds are different in different types of cells. I will investigate how the DNA folds and how the changes in the DNA alter the way genes are regulated in cells from RA patients. This will provide information on the cause of disease and will suggest new options to treat RA, providing better patient care and improved outcome.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE
Title: Proteostasis and Autophagy in Immune Senescence
Funder: Wellcome Trust

Abstract: Lymphocyte function underpins effective immunity to infection and cancer, and is adversely affected by age in a process called immune senescence, a major obstacle to having a healthy lifespan. The cellular basis of T cell senescence is largely unknown. Maintaining proteostasis, regulated by protein synthesis and degradation, in the face of intrinsic and environmental insults is a key determinant of cellular and organismal lifespan. We will address the hypothesis that modulating the conserved degradation and recycling process known as autophagy, can restore immune responses in lymphocytes in the elderly. We have shown that autophagy prevents immune aging, and demonstrated a decline in autophagic flux in lymphocytes with age, and a global age-related decline of protein translation. But it is uncertain which of the synthesized and degraded proteins are most important. It is clear, however, that the induction of specific repair pathways, including autophagy, extends life and health span. We have uncovered a novel pathway that rejuvenates lymphocyte function by regulating autophagy translationally, which we intend now to fully characterize. Our goal is to identify potential therapeutic strategies for restoring health span in the elderly. This work will also address fundamental gaps in our understanding of the aging process.

Lay abstract: Healthcare challenges are intensifying as our population ages. Age is the biggest single risk factor for many debilitating diseases, from infections to cancer. Immune aging contributes by preventing useful immune responses, but this process is little studied. Autophagy, a pathway activated when cells are stressed, clears away debris accumulated over time, recycling building blocks for re-use. Declining autophagy underpins aging in many tissues, especially, as we have shown, in the immune system. We now want to identify what is degraded and what is generated by autophagy, to better understand how it prevents aging. We will study how autophagy controls the amino acid pool and cellular energy levels. While protein synthesis levels decline with age, we recently found that increasing the synthesis of autophagy proteins alone rejuvenates immune cells. By studying this pathway, we hope to identify new ways to prevent or even reverse the aging of our immune cells.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE
Title: Integrative Transport Phenomena in Chemokine Gradient Establishment
Funder: Wellcome Trust

Abstract: A functioning immune system relies on carefully tuned fluid, cellular and molecular transport processes. Chemokines are secreted chemoattractants that orchestrate the migration and positioning of leukocytes, and are indispensable components of all protective and pathogenic immune and inflammatory responses. Lymphatic endothelial cells (LECs) play a prime role in chemokine production and exchange with the surrounding tissues, where a combination of diffusion, advection, binding kinetics and cellular uptake result in the generation of spatial chemokine gradients that govern leukocyte migration. If chemokine gradients are not appropriately tuned, leukocytes fail to respond and immune responses are compromised. While previous research has revealed much about chemokine function at the sub-cellular level, there is little quantitative knowledge of how physical and biological mechanisms interact to produce functional chemokine gradients in vivo, or of how the specific characteristics of those gradients affect leukocyte behaviour. We aim to develop a comprehensive quantitative knowledge base of chemokine gradient formation and regulation using integrated experimental and modelling approaches. This will provide unprecedented insight into this complex, dynamic and critically important process, and has potential impact on vaccination and on the treatment of diseases with key immune cell contributions, such as allergy, autoimmunity, cardiovascular disease, and cancer.

Lay abstract: White blood cells protect us from infection, but also contribute to the development of many diseases, such as asthma, arthritis, heart disease and cancer. To do this they have to be able to get out of the blood and move around inside our organs. This cell movement is guided by chemokines. These are attractant molecules that are released by cells and form ‘chemokine concentration gradients’ inside the tissues of our organs, with the highest concentration near the cell releasing the chemokine. White blood cells sense these gradients and move towards the source of the chemokine. If the gradients are not set up correctly, then white blood cells have trouble finding their way. This can have profound consequences in health and disease. It is important therefore that we understand the complexities of how chemokine concentration gradients are set up, maintained and controlled, and develop a better appreciation of how they make white blood cells move. The combined expertise of our multidisciplinary team of biologists, engineers and mathematicians will provide unique insights into these processes, and their findings could ultimately benefit many areas of medicine.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE
Title: Engineering a Functional Synthetic Thymus
Funder: Wellcome Trust

Abstract: T-cells, the central executors of adaptive immunity, are generated in the thymus. Thymus biology is intricate, reflecting the complex processes that control its seeding with haematopoietic progenitors, and subsequent T-cell commitment, differentiation and repertoire selection. Physiological T-cell repertoire development and selection is not yet possible outside the native organ. Recent advances, including the advent of T-cell immunotherapy, have brought thymus biology into the spotlight, and the capacity to recapitulate and control thymus function would open enormous possibilities for novel immune-mediated therapies for cancer, inflammation, immunodeficiency and autoimmunity. Our collaborative aim is thus to create a fully functional, synthetic, thymus organoid, as a tractable enabling system for basic research and a therapeutic source of functional T-cells. To achieve this, we will decipher the molecular and cellular mechanisms that control development and function of the epithelial cell compartment of the thymic stroma which provides the organ’s specialist functions by integrating cutting-edge stem cell biology with biomaterials engineering, single cell time-and-space-controlled transcriptomic interrogation and advanced mathematics. The project outputs will be transformative for understanding the synthetic formation of a primary lymphoid organ and for studies of T-cell maturation with its translational potential for new immunotherapeutics including thymus replacement or regeneration.

Lay abstract: T-cells, a type of white blood cell, are required in our immune system to fight infection and are made in a special organ called the thymus. The thymus produces a pool of T-cells that protects our bodies from infection and cancer, but does not attack our bodies to cause autoimmune diseases. The processes through which it does this are complex and it is not yet possible to make equivalent T-cell pools in the lab. It has recently become possible to use T-cells as therapies to control cancer. If we could recreate a functional lab-grown thymus, this would allow us to make normal T-cell pools, and would open possibilities for discovering new therapies. Our aim is therefore to create a fully functional thymus in the lab, by using stem cell technology together with tissue engineering. Once created, this ‘synthetic thymus’ would open enormous possibilities for basic research and new T-cell therapies.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE
Title: Immunomatrix in Complex Disease (ICD)
Funder: Wellcome Trust

Abstract: Immune and inflammatory processes underlie virtually all major human diseases we now face. Similarly, dysregulation of the extracellular matrix (ECM) is a central process in the pathogenesis of chronic diseases. The molecular, physical and mechanical properties of the ECM regulate immune cell mobility, survival and function. In turn, the immune system is required to maintain and regulate healthy matrix and restore matrix integrity following injury. Together, the ECM and the immune system define tissue health, with failure leading to disease. However, matrix biology and immunology are typically studied independently and progress in understanding and treating disease is hindered by both immune system and tissue complexity. Our goal is thus to train a new generation of scientists to embrace tissue and disease complexity. By understanding the inter-connectivity between matrix and immune function they will make discoveries that help unravel complex disease. The programme will: 1) Provide an intensive taught component of immunomatrix, tissue complexity and multimorbidity 2) Deliver a bespoke training programme in bioinformatics 3) Offer intellectually challenging cross-disciplinary PhD projects utilising state-of-the art technology 4) Enrich student experience through optional "Silo Switches" into allied careers 5) Provide active mentoring, and the experience of mentoring others


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE
Title: The troubled immune system - molecular origins of immune dysregulation
Funder: Wellcome Trust

Abstract: Immune-mediated inflammatory disease is a major and increasing cause of ill health worldwide. Effective therapy is hindered by our incomplete understanding of immune regulatory mechanisms and how to manipulate them. In this research project, we will focus on the molecular dissection of early onset immune dysregulation as a means to identify relevant genes and pathways in an unbiased way. We will use next generation sequencing to uncover causative mutations in children manifesting autoimmunity, autoinflammation and lymphoproliferation, sometimes in a familial way. We will characterize the diseased immune system in fine detail, using state-of-the-art technologies to learn as much as possible from small volumes of patient blood and tissue. We will study the role of the encoded proteins in vitro, modeling the effect of mutations and exploring the associated immunobiology. Finally we will create and study knock-in mouse models in which hypomorphic patient mutations are precisely engineered into the homologous murine gene. By these means we will gain maximal mechanistic insight from these experiments of nature, improve diagnostic and therapeutic outcomes for our patients and empower the development of new and better approaches to therapy of other immune-mediated inflammatory diseases.

Lay abstract: The human immune system draws on a wide range of powerful weapons to protect us against infection. It stands to reason that those weapons also pose a threat if mistakenly targeted to our own tissues, so the healthy immune system is actively held in check. When immune regulation breaks down, we see diseases like rheumatoid arthritis, inflammatory bowel disease and insulin-dependent diabetes. To learn more about the mechanisms underlying immune regulation, my research will focus on a special group of patients. These are children who develop severe problems with self-directed immune responses early in life. Experience suggests that most of these children have an inherited problem with their immune system. In our research, we will sequence patients’ DNA to find the genetic spelling mistakes that cause these problems. We will try to work out how the affected genes take part in proper regulation of the immune system. Using modern techniques, we will look in great detail at immune cells from patients and healthy people. We will sometimes study the immune system of mice with similar genetic spelling mistakes to give us more insight. By describing new diseases of the immune system and their mechanism, our research will improve patient outcomes.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Structural studies of BRISC-regulated immune signalling
Funder: Wellcome Trust

Abstract: Cells maintain protein homeostasis by adding a small protein, ubiquitin, to regulate a variety of cellular processes; dictating protein activity, localisation or degradation by the proteasome. The addition of ubiquitin, known as ubiquitylation, is a reversible process making it a versatile post-translational modification aptly suited for cell signalling. Removal of ubiquitin is catalysed by deubiquitylating enzymes, commonly referred to as DUBs. I will explore the structure and function of the BRISC (BRCC36-isopeptidase complex) DUB, by combining structural, biophysical and biochemical techniques to elucidate how this multi-protein complex critically regulates immune signalling. Specifically, I will use cryo-electron microscopy (cryo-EM) to elucidate the interaction of BRISC with a novel binding partner, EPS15 and with its native substrate, poly-ubiquitin. BRISC is also an attractive therapeutic target for autoimmune diseases. High-throughput screening has identified small molecule inhibitors of BRISC enzymatic activity in vitro. Exploiting structural techniques (cryo-EM, NMR), I will define the mode of inhibition exhibited by these molecules. Exploring these key mechanisms will expand current knowledge of inflammatory signalling pathways and establish how these can be therapeutically targeted to combat autoimmune disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Role of the transcription factor Ikaros in shaping chromatin dynamics of gene activation and repression
Funder: Wellcome Trust

Abstract: In multicellular organisms, lineage-specific transcription factors (TFs) initiate gene expression programmes that direct differentiation and confer distinct cellular identities. This requires regulation of the chromatin environment involving specific changes in chromatin accessibility, epigenetic modification, and chromatin contacts at regulatory regions. The molecular basis through which TFs drive these processes to activate some target genes and repress others is not fully understood. This project studies how the haematopoietic TF Ikaros binds target elements and modulates chromatin to establish the precise transcriptional programmes required for B-cell differentiation. Key goals are 1) understand how the arrangement of Ikaros binding-motifs at regulatory elements interplays with Ikaros dimerisation/multimerisation to regulate binding 2) determine if recruitment of the chromatin remodeller CHD4 by Ikaros is required for chromatin accessibility and transcription and 3) identify the factors recruited by Ikaros which mediate gene activation or repression. A combination of single-molecule FRET, genomics, and biochemical/proteomics techniques in conjunction with the availability of mutants will be employed to address these aims. Mechanistic insight into Ikaros function will be a basis towards our understanding of the general principles through which TFs direct transcription and pathways critical for normal B-cell differentiation that are dysregulated in B-cell malignancies.

Lay abstract: All cells of our body share the same genetic code (DNA), but different cells and tissues perform different functions. It is actually the gene expression pattern (which genes are on or off) that give cells distinct functionalities. Specific gene expression patterns are established during a process of cellular differentiation, where stem cells become more specialised cells. During differentiation, regulator proteins called transcription factors binding to specific target genes and recruit other co-regulator proteins to control the expression of these genes. Using a combination of biochemical/biophysical techniques, I want to understand how transcription factors bind target genes and what proteins are recruited that allows them to drive the correct gene expression programs during differentiation. Studying the mechanisms underlying gene expression is critical if we want to understand how these pathways are perturbed in disease, and enable the development of therapeutics that can correct gene expression without altering the DNA.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Control of T cell responses by accessory receptors revealed by phenotypic models
Funder: Wellcome Trust

Abstract: T cells orchestrate immune responses crucial for the elimination of infections and cancers. They do this by initiating a diverse set of effector responses when their T cell surface receptors (TCRs) recognise these threats. It is now appreciated that a large number of other, “accessory”, receptors shape these responses. Indeed, the remarkable clinical success of checkpoint inhibitors and chimeric antigen receptors is based on perturbing accessory receptor signalling. Despite extensive research into the underlying biochemistry, we have yet to formulate canonical models of signalling that can predict how accessory receptors shape T cell responses. Here, we propose to use a mathematical method known as adaptive inference to identify signalling models directly from T cell response data, without prior biochemical assumptions. The method produces what we term "phenotypic models" because it coarse-grains over molecular information. These models provide effective pathway architectures showing how accessory receptors integrate (or not) with TCR signalling to shape response phenotypes. This will move the field beyond the current stimulatory/inhibitory binary paradigm of accessory receptors. The work offers a different way to study receptor regulated signalling pathways and the predictive power of the phenotypic model will be exploited for T cell-based therapies.

Lay abstract: T cells are important immune cells responsible for fighting infections and cancers. They continuously scan other cells for these threats using a molecule on their surface called a receptor. Basic research has shown that, besides the main receptor, other ‘accessory’ receptors also control how T cells respond. Precisely how is unknown. There has been a focus on identifying the molecular parts that process information from receptors, with the goal of, for example, improving T cell therapies for cancer treatments. This has revealed enormous complexity but has not greatly improved our understanding of how T cells are controlled. We plan to study accessory receptors from a different point of view, similar to how a pilot may learn to fly an aircraft: Instead of studying the detailed parts, we study how triggering accessory receptors (i.e. moving cockpit levers) changes the T cell response (changes aircraft flight). This will lead to a more precise understanding of how all receptors work together to control T cells. We will use this understanding for the benefit of human health (i.e. flying the aircraft safely through all conditions).

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