NIHRDataInsights/HRCSData huggingface dataset:
Title: Thymus transplantation for the treatment of Complete DiGeorge syndrome.
Funder: Wellcome Trust

Abstract: Babies with severe DiGeorge syndrome lack white blood cells called T-cells. T-cells are essential to immunity because they fight infectious diseases and also instruct other types of white blood cell to fight infection. Therefore, DiGeorge babies who lack T-cells have a very short life-expectancy without treatment, and die before 2 years-of-age because of lack of immunity. Severe DiGeorge syndrome patients cannot make T-cells because they lack an organ called the thymus gland, in which these cel ls are normally generated. Therefore, one way to treat DiGeorge syndrome is to transplant a thymus. The thymus tissue is obtained from infants undergoing cardiac surgery, when it is necessary to remove tissue to gain access to the heart. This thymus tissue would normally be discarded. This project aims to improve the technology for thymus transplantation. We will find out if it is better to tissue-match the transplanted thymus with the tissue-type of the patient. Given that tissue-matching thymus transplants would be difficult because the severe DiGeorge patients would not survive while an appropriate tissue-matched donor was found, we will find out if we can use gene therapy to modify the tissue-type of the thymus that will be transplanted instead of tissue-matching.


Research activity codes: 5.4 SURGERY
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;DISPUTED AETIOLOGY AND OTHER
Title: A phase II trial of Tocilizumab in anti-TNF refractory patients with JIA associated uveitis (APTITUDE)
Funder: Versus Arthritis

Abstract: Primary objective: The primary objective of this trial is to estimate the response rate to Tocilizumab in combination with MTX in children with JIA-associated uveitis and to determine whether further research into the use of this intervention for the treatment of anti-TNF refractory JIA-associated uveitis should be conducted. Secondary objectives: To conduct a preliminary evaluation of the short term safety and tolerability of Tocilizumab in combination with MTX, with regards ocular complications of treatment, adverse events and laboratory assessments To assess the efficacy of treatment with Tocilizumab to permit concomitant medication reduction, in particular topical and parenteral steroids


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;EYE
Title: Gene therapies for age-related macular degeneration and uveitis
Funder: Wellcome Trust

Abstract: Adeno-associated viral (AAV) vector-mediated retinal gene therapies have demonstrated efficacy and safety in the treatment of inherited retinal dystrophies. We aim to combine established AAV gene delivery platform with CRISPR/Cas9 genome editing and immunomodulation to treat two major causes of severe sight impairment: age-related macular degeneration (AMD) and non-infectious uveitis. While the pathogenesis of dry AMD remains uncertain, there is evidence to suggest that amyloid-&beta;, a toxic peptide resulting from alternative cleavage of amyloid precursor protein (APP), may play a central role in linking various known risk factors and initiating innate immune responses that lead to retinal pigment epithelial (RPE) degeneration. To test this hypothesis, we will use an AAV-delivered CRISPR/Cas9 vector to disrupt APP gene in the retina and test its effects on AMD progression and amyloid-&beta; knockdown in mice and non-human primate (NHP) models, respectively. In addition, we will investigate the in vivo genome editing efficacy and innate immune responses to CRISPR guide RNA and Cas9 endonuclease in the NHP retina. Finally, as a novel strategy for controlling chronic intraocular inflammation in uveitis, we will test whether AAV-mediated expression of a key T-cell immune checkpoint regulator could suppress retinal inflammation in a mouse model of uveitis.

Lay abstract: Age-related macular degeneration (AMD) and uveitis are major causes of blindness worldwide. We will use a harmless virus, called AAV, to specifically disable a disease-causing gene in the retina whose product is thought to play a central role in macular degeneration. The efficacy and safety of this approach will be tested in animal models, which will also provide the opportunity for an in-depth analysis of immune responses to gene editing and optimising the surgical technique for delivering gene therapy to the retina in future clinical trials. In addition, we will design and test a new treatment for uveitis. This will use AAV to deliver an immunomodulatory signal to the retina which could dampen down immune cell-driven chronic inflammation in the eye. This project will improve our understanding of the fundamental mechanisms underlying AMD and ocular ‘immune privilege’, and lead to potential new treatments for common retinal diseases.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;EYE
Title: Investigating the mechanisms of peptide repertoire selection by TAPBPR
Funder: Wellcome Trust

Abstract: The tapasin homologue TAPBPR is a peptide editor in the MHC class I antigen presentation pathway. It is thought to act as a quality control component of the pathway, and it shapes the presented peptide repertoire of cells. However, the peptide editing activity of TAPBPR varies between different MHC class I molecules. It has been shown that TAPBPR shows a preference for certain allomorphs, including HLA-A molecules and MHC class I molecules which bind peptides with a hydrophobic C-terminus. During my PhD I will use immunopeptidomics to explore this aspect of TAPBPR biology. By knocking out TAPBPR and performing exogenous peptide editing on cells expressing different MHC class I molecules, I will investigate the effect of different TAPBPR functions on the peptidome presented by different MHC class I molecules. This will inform our understanding of the function of TAPBPR in the immune system in the context of different MHC class I molecules, and thus of its role in shaping the immune response of different individuals and populations. I will also investigate the possibility of using TAPBPR-antibody fusion proteins, which have been shown to perform efficient and targetable peptide exchange at the surface of cells, as therapeutics.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE
Title: Investigating the role of mTORC1 signalling in cellular migration
Funder: Wellcome Trust

Abstract: Rapamycin is a drug currently used to treat some cancers and to prevent organ rejection. In yeast, flies, fish and mice, rapamycin improves both healthspan and lifespan, and therefore makes it a promising anti-ageing treatment. However, long-term treatment with rapamycin is associated with numerous side-effects such as decreased wound healing, making it unsuitable for an anti-ageing treatment in humans. The “mechanistic target of rapamycin” (mTOR) pathway is a vital cellular pathway. It is involved in the regulation of cellular growth and protein synthesis. Rapamycin is an inhibitor of the mTOR pathway and rapamycin or inhibition of mTOR has been shown to decrease cell movement. We have recently described a distinct pool of mTORC1 activity at the edge of the cell, in an area important for movement. We hypothesise that inhibition of mTORC1 by rapamycin prevents the formation of proteins required for cell movement leading to reduced wound healing. My project aims to investigate the role of mTORC1 in cell movement, to see if we would ever be able to use rapamycin as a human anti-ageing treatment.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE
Title: Molecular and functional analysis of human induced pluripotent stem cell derived tissue resident macrophages
Funder: Wellcome Trust

Abstract: Tissue-resident macrophages (TRM) have crucial roles in development and tissue functions, many of which are not well defined. Interestingly, certain genetic defects and pathogens demonstrate selective affinity for specific human TRMs. For instance, mycobacterium tuberculosis preferably affects and survives better in TRMs residing in the lungs, but not those in other organs. To shed light on their organ-specific functions and unique disease biology, we wanted to unravel the molecular mechanisms underlying human TRM identity. However, the current understanding of human TRMs is based on monocyte-derived macrophages, which constitute only a subpopulation of TRM in tissues, and mice TRMs, which introduces significant inter-species differences in our knowledge. We aim to derive TRMs from human induced pluripotent stem cells through 3 complementary approaches: 1) adding defined growth factors in culture medium, 2) genetic engineering to induce TRM fate programme, and 3) co-culturing with 3D organoids. Then, we examine whether epigenetics and metabolic landscapes form the determinants of TRM cell fate using ATAC-seq, NMR and gene editing techniques. Based on the understanding, we will genetically engineer macrophages with enhanced functions, and assess their engraftment and safety in preclinical disease models to pave the way for their clinical use as advanced therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE
Title: Reprogramming the epigenome: erasing memory and creating diversity
Funder: Wellcome Trust

Abstract: Epigenetic memory needs to be globally reprogrammed in the early mammalian embryo for cells to attain broad developmental potency including naïve pluripotency. Exit from pluripotency in turn requires rapid establishment of epigenetic memory in the form of epigenetic priming. This involves both ‘activating priming’ whereby lineage specific genes are protected from repressive marking to safeguard their future transcriptional activation during tissue and organ development, and ‘repressive priming’ by which genes of a different lineage are suppressed. These large-scale dynamics raise fundamental questions about the impact of epigenetic memory on pluripotency and differentiation, which we address in this research programme. First, we will attempt to disable global demethylation in vitro and in vivo by manipulating the epigenetic coordinator UHRF1 at the transcriptional and posttranscriptional levels. Second, using genetic and epigenetic manipulation we will determine the mechanisms and downstream consequences on lineage and tissue development of ‘activating priming’ factors we have recently identified. Third, we will investigate the role and targets of ‘repressive priming’ and epigenetic heterogeneity in cell fate decisions and lineage development. New insights gained into memory erasure and epigenetic determinants of cell fate will illuminate and guide strategies for using ES, iPS, and multipotent stem cells in regenerative medicine.

Lay abstract: Embryo development is a remarkable process. Following fertilisation of the egg by the sperm, the embryo must grow from a single cell capable of becoming any part of the body to ordered tissues each with their own identity. This requires tight regulation however we have a limited understanding of how this operates. We have developed new technologies that enable us to research this important time in embryogenesis. We aim to understand how the genes in our DNA are marked by small chemical additions. We will study how the early embryo re-sets these marks, providing a clean-slate from which to build a new organism. We will investigate how different genes are subsequently marked as active or silent in different cells as their identity starts to form. By understanding the mechanism of gene regulation during development, we can ensure healthy development of embryos, and will have important impacts in regenerative medicine.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE
Title: Expanding the druggable proteome of immune cells - towards synthetic immune regulation
Funder: Wellcome Trust

Abstract: Drugs capable of manipulating the innate immune system have the potential to treat a broad spectrum of human diseases. However, to realise this potential, we need both a better understanding of the biological processes that regulate innate immunity and to radically expand the scope of potentially druggable protein targets. My research will address both these limitations. I will use activity-based protein profiling to identify proteome-wide sites of ligandability in primary human immune cells and drive the development of frontier chemical probes, which can be used to dissect the principles of immune regulation or provide leads for drug development. In particular, my research will focus on proteins involved in non-degradative ubiquitylation, a critical pathway mediating signal transduction in innate immunity. My specific aims are to: 1. Map the interactions of small molecules with proteins in primary human innate immune cells on a proteome-wide scale. 2. Develop targeted mass spectrometry and synthetic biology platforms to efficiently verify, establish structure-activity relationships and explore the functional consequences of small molecule-protein interactions. 3. Develop high-quality chemical probes for proteins that play critical roles in innate immunity. This research will provide the scientific community with the resources to embark on a new era of targeted immunotherapy.

Lay abstract: Drugs capable of precisely manipulating the immune response have the potential to treat a broad spectrum of diseases, including chronic inflammation and infection, neurodegeneration and cancer. However, to realise this potential, we need to both better understand how the immune system is regulated at the molecular level and how it can be manipulated by drugs. In my research, I will use a combination of reactive small molecules and mass spectrometry to uncover new drug targets in immune cells. I will also develop protocols to efficiently verify and explore how the binding of small molecules to proteins affects immune function. I will particularly focus on identifying ways to manipulate intracellular communication networks that rely on a small protein called ubiquitin. The outcomes of my research will guide the development of chemical tools which can be used to dissect the principles of immune regulation and inform the design of novel immunotherapy drugs.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE
Title: Discovering how transcription factors define human B cell fate decisions in vivo.
Funder: Wellcome Trust

Abstract: The development of antibody-producing plasma cells and memory B cells (MBCs) is essential for immunological memory, yet the transcriptional mechanisms that regulate these different B cell fates are poorly understood. One reason for this is the highly dynamic and heterogeneous nature of B cell maturation and differentiation. This challenge can be overcome using single-cell genomics approaches to examine gene expression networks within rare transitional cell states and hence identify regulatory transcription factors (TFs) that shape B cell fate decisions. I will therefore apply single-cell approaches to primary human B cells to discover the gene regulatory mechanisms that drive human B cell fate choices. Briefly, I will: 1. Discover TFs linked with B cell fate decisions in vivo using single-cell genomics 2. Determine how these TFs compete or work together during cell fate commitment by mapping their genome-binding patterns 3. Functionally dissect how these TFs drive gene expression to define MBC differentiation This will comprehensively identify the TFs and regulatory mechanisms that define gene expression patterns associated with human B cell fate decisions in vivo and will therefore represent an important advance in our understanding of human B cell biology and how immunological memory is achieved.

Lay abstract: B cells are immune cells that are important to human health. When B cells respond to pathogens they can differentiate to plasma cells, which make antibody, or memory B cells, which protect against future infections. The decision to make a memory B cell or a plasma cell is controlled by transcription factors that regulate gene expression. However, we don’t fully understand the mechanisms by which transcription factors do this. I will use cutting-edge single-cell genomics methods to examine transcription factor activity during human B cell development at unprecedented resolution. This will allow me to discover how different transcription factors regulate gene expression to control B cell fate decisions (ie. memory B cell vs plasma cell) and reveal how different transcription factors work together or compete with another during this process. This will be important to develop methods to modify B cell development to improve vaccine efficiency or treat auto-immune disorders.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE
Title: DrosophiLAP: a live in vivo study of LC3-Associated Phagocytosis
Funder: Wellcome Trust

Abstract: My research proposal aims to better understand LC3-associated phagocytosis (LAP) by exploring it for the first time in real-time in a living organism: Drosophila.During the first four months in the Wood lab, I have demonstrated that LAP occurs in fly macrophages, and that these are a suitable experimental system to monitor LAP in real-time while in vivo.I am now committed to achieving four goals. 1. To clarify LAP's cargo specificity in vivo: is LC3 recruited to all phagosomes, regardless of the nature of engulfed particles? To do so, I will assess LC3 recruitment to phagosomes engulfing apoptotic or necrotic debris, both generated at wounds. 2. To understand whether LAP has a role in macrophage priming: is it required to instruct naive macrophages on how to recognise immunogenic cues? To do so, I will perturb LAP and assess the effects on macrophage ability to recognise immunogenic stimuli. 3. To discover whether adipocytes rely on LAP to fulfil their biological roles. To understand this, I will monitor LC3 dynamics in adipocytes engulfing cell debris at wounds. 4. To explore the LAP/autophagy cross-talk: do the two processes compete for LC3? To clarify this, I will investigate how perturbing autophagy impacts LAP and vice versa.

Lay abstract: Cells utilise phagocytosis to eat and autophagy to survive food scarcity. The two processes were only recently found to share part of their machineries: LC3, a key autophagy player, is also involved in phagocytosis. The newly-identified LC3-associated phagocytosis, or "LAP", occurs in immune cells (e.g. macrophages), and regulates the immune response. Our understanding of LAP is currently limited by the lack of a model to monitor this process in living organisms, and to assess the effects of LAP perturbation in real-time. To overcome this, I will perform live-super-resolution microscopy to visualise LAP occurring in macrophages within living Drosophila (fruitfly) embryos. This will allow me to understand whether LAP is important for innate immune priming, the process that renders macrophages able to recognise wounds and fight pathogens. Importantly, using a complex organism like Drosophila will give me the chance to explore whether other types of cells (eg. adipocytes) also perform LAP.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE
Title: Study of the dark proteome in innate immunity
Funder: Wellcome Trust

Abstract: Intrinsically disordered proteins/domains (IDPs/IDRs) are highly flexible and lack a defined secondary or tertiary structure. Their highly reactive and versatile interaction surface contains diverse small linear motifs that enable IDP/IDRs to act as key regulatory protein interaction and signalling hubs. In addition, a new set of small proteins have recently emerged by the identification of thousands of microproteins or smORF-encoded peptides (sPEPs) from which a few validated sPEPs play crucial regulatory roles via protein-protein interactions and add a new regulatory dimension to multiple cellular processes. Due to the size of sPEPs and high flexibility of IDPs, conventional tagging, biochemical and cell biological approaches are not suitable for the study of these type of proteins. I will overcome this by implementing a pipeline to achieve the orthogonal site-specific incorporation of minimally invasive non-canonical amino acids in IDPs and sPEPs. With this approach I aim to study the protein-protein interaction networks, localization and function of IDPs and sPEPs involved in innate immune processes such as the antiviral response or neutrophil defense mechanisms against pathogen invasion.

Lay abstract: The innate immune system is comprised of different cell types which contain diverse evolutionary adapted protein-protein interaction networks that sense and trigger tailored responses to identified threats. These processes require a tight regulation in order to achieve an adequate immune defence and avoid immune-mediated pathology due to an uncontrolled immune response. Intrinsically disordered proteins/regions (IDP/IDRs) are highly dynamic flexible proteins that lack a defined structure and have been shown to be key signalling and protein interaction hubs due to their large interaction surface enriched in small linear binding motifs. Multiple proteins involved in the innate immune response contain IDRs of variable lengths. However, very little is known of their functional role and their interactome. I plan to use state-of-the-art chemical biology, biochemical and cell biological approaches to understand the functional relevance of IDPs in innate immunity which could lead to the finding of new therapeutic targets.

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