NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Defining a specific IL-22-mediated pathway in regulating eczema
Funder: Chief Scientist Office, Scotland

Abstract: Eczema is a debilitating condition which has become commoner in the last 30 years. There are several sub-types of eczema, each with varying immunological abnormalities, including atopic eczema, allergic contact dermatitis (ACD), and acute and chronic eczema. Chronic eczema shares some immunological abnormalities with psoriasis. In order to effectively treat patients with eczema in the future, we need a better understanding of the underlying immune abnormalities.
Objectives and outcomes:
1: To assess if the Prostaglandin E2/IL22 pathway varies with types of eczema comparing this with psoriasis.
Interleukin 22(IL22) is a recently identified functional protein produced by immune cells (T cells), which is closely linked to eczema development. IL22 can be stimulated by another inflammatory chemical called Prostaglandin E2 (PGE2) to cause allergic contact dermatitis (ACD) in a mouse model.1 To establish if this also occurs in human ACD I will take blood samples and skin biopsies from eczema and psoriasis patients and from controls to study these chemicals.
2: Does T cell response to PGE2 differ in eczema patients?
PGE2 causes chronic skin inflammation by increasing production of IL22 from T cells.  I will study whether the T cell response to PGE2 in eczema patients is by the same signalling pathway as occurs in other systems by studying skin taken at biopsy.
3: What is the sequence of events of activation of the PGE2/IL22 pathway? 
To study this I will recruit human volunteers in whom I will produce irritant and allergic eczemas, measuring PGE2 and IL22 at various time points. Repeating the experiment I will create two groups, one pre-treated for one week with a non-specific prostaglandin inhibitor (aspirin) and the second with a placebo control.
Benefits: If I can identify different pathways according to eczema subtype this would help development of disease-specific treatments with fewer side effects while reducing costs to the health services.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: SKIN
Award Title: Defining and diagnosing neurodegenerative Movement Disorders through integrated analysis of Genetics And neuroPathology (MD-GAP)
Funder: Medical Research Council

Abstract: The integration of genetics with imaging has led to major insights into brain development and neurodevelopmental disorders.  Late onset neurodegenerative disorders are associated with abnormal protein aggregates which define and drive the disease, and so integration with neuropathology is the logical approach to these conditions.   We will obtain DNA from ~ 2500 individuals with pathologically defined neurodegenerative movement disorders and ~ 1000 controls.  In collaboration with the MRC UK Brain Banks Network (BBN) we will collate initial clinical diagnosis, pathological diagnosis, age at onset, gender and survival.  We will collate Braak and Thal pathological stage data reflecting the extent of three major neurodegenerative disease pathologies - tau, alpha-synuclein and amyloid.  In a subset of 750 Lewy body disorder spectrum cases we will use digital pathology approaches to quantify the amyloid, tau and alpha-synuclein burden in three important representative areas: frontal cortex, entorhinal cortex and cingulate gyrus.  We will genotype each case and control using the Illumina MegaEX / Neurochip v3 single nucleotide variant array.  This will provide information on genome wide common variation in individuals with different ancestries; risk variants from genome wide association studies (GWAS) and neurodegenerative rare variants.  We will define the genetic drivers of pathology based on candidate gene/transcript analysis, and with hypothesis free GWAS.  We will correlate genetic data with clinical data including survival, rate of progression and dementia.  We will carry out pathologically defined genome wide association studies, which will be meta-analysed with pathologically defined GWAS from around the world, and use the data to develop polygenic risk tools to enhance diagnostic accuracy.  Genetic data will be made available via the BBN database to enable future exploration of the downstream effects of genetic variation by bona fide investigators.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Defining descending inhibitory pathway functionality in health and disease
Funder: Medical Research Council

Abstract: Descending modulatory controls project from the brainstem to the spinal cord to inhibit or facilitate pain sensations. In health the descending pain modulatory system (DPMS), which encompasses a unique form of descending control termed diffuse noxious inhibitory controls (DNIC), may act endogenously to inhibit spinal neuronal processing and thus reduce the final percept of pain. However maladaptive activity in the DPMS has been reported in rodent models of chronic pain and I have published evidence that DNIC pathway expression, quantifiable as a reduction in spinal nociceptive processing upon application of a noxious conditioning stimulus, is dysfunctional in rodent models of chronic pain.  For this NIRG application I have collected pilot data to evidence that the DNIC pathway originates in the A5 nucleus and that DNIC expression is negatively impacted by excitation of the locus coeruleus (LC). My working hypothesis is that while the DPMS (LC projection) and DNIC (A5 projection) pathways influence one another in health, they are functionally separate and evolutionarily distinct and that they influence one another differentially in a disease state. If correct, the DPMS and DNIC pathways offer 2 separate therapeutic targets in disease. I have shown that in early stage cancer induced bone pain rats DNIC is dysfunctional. I want to know does the functional relationship between the A5 and LC nuclei change in these animals? I will investigate brainstem reciprocal crosstalk and spinal pharmacological functionality in healthy and early stage CIBP rats in order to potentially reveal a novel underlying mechanism of pain.  Altogether, the research proposed in this application will enable me to gain mechanistic insight of pain inhibition pathway malfunction in disease. This insight is crucial for the eventual development of targeted therapeutic strategies that act to boost endogenous descending inhibitory pathway activity.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Defining mechanisms of hormone-dependent cancer disease progression
Funder: Cancer Research UK

Abstract: Background: Hormone-dependent cancers constitute two of the most common cancer types (ER+ breast and prostate cancer). Treatments that block the driving transcription factors, ER in breast and AR in prostate, have improved survival rates substantially, but treatment resistance is a common clinical problem. The core cell-type defining transcription factors have been identified in primary disease and include pioneer factors such as FOXA1 and a number of co-regulatory proteins and associated transcription factors. Recently, proteomic and genetic screens have linked numerous additional factors with these transcriptional complexes.

Aims: The central aim is to define the biological processes and the critical changes that contribute to endocrine-resistant, metastatic disease. This will involve the discovery of genes and proteins involved in breast cancer metastasis, the identification of the role of key pioneer factors in this process and analysis of the role of specific mutations in treatment response and metastasis. We will also explore a hypothesis around the role of FOXA1 in prostate cancer progression.

Methods: The proposal builds on a wealth of background information and novel methodological tools, to enable an unbiased and global investigation of the key events that contribute to ER/FOXA1 transcriptional activity in breast cancer and AR/FOXA1 transcriptional activity in prostate cancer. The work will identify key genes and associated proteins that influence tumour progression, it will explore the functional interaction and dynamics between known, but uncharacterised co-regulatory proteins, it will exploit global CRISPR screens and a method we developed called qPLEX-RIME, which permits unbiased discovery of protein interactomes from clinical samples. In addition, the work will exploit a contemporary and clinically relevant in vivo model of luminal breast cancer metastasis. As a community, we have been studying primary breast for decades, but our understanding of the events that drive metastasis are poorly understood. This is in large part because we have been unable to accurately and faithfully model luminal (ER+) breast cancer metastasis and there has been limited access to metastatic samples. The advent of the intraductal tumour engraftment (MIND) system, provides the first reliable and physiologically relevant approach for studying ER+ breast cancer metastasis.

How the results will be used: The measurable endpoints of this proposal will be the identification of the critical components in the transcriptional complex, an understanding of the events that drive metastasis, clarity around the impact of specific mutational events on this process and new insight into potential ways of therapeutically intervening in these contexts.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Defining new treatment and headache mechanisms in raised intracranial pressure
Funder: Sir Jules Thorn Charitable Trust

Abstract: The research will also provide the first insight into fundamental headache mechanisms and guide additional approaches to treatment.Furthermore, the results are highly relevant to other conditions of raised brain pressure (traumatic brain injury, hydrocephalus (excess fluid on the brain) and space-flight intracranial hypertension).

Lay Abstract: Idiopathic intracranial hypertension (IIH) is a debilitating condition characterised by raised intracranial pressure (ICP) and has been overlooked for decades – resulting in no targeted treatments. It causes severe headaches and potential blindness. Predominantly occurring in obese young women, the incidence is rising rapidly in line with the global epidemic of obesity, driving escalating healthcare costs. Patient voice and quality-of-life studies highlight that IIH headaches are the overwhelming long-term disabler, yet mechanisms and potential treatments are not established. My research has established a new target to lower ICP through glucagon-like peptide 1 receptor agonism with Exenatide (an existing diabetic drug). Exciting preliminary data has demonstrated a reduction in ICP and headache in IIH patients. Building on this discovery science, this translational study will evaluate the efficacy of repurposing Exenatide to treat IIH and reduce headaches through a randomised controlled trial that would lead to drug licencing and translation to patient care upon successful completion. Linkedmechanistic evaluation in human and mouse models will interrogate the relationship between ICP, headache mechanisms and therapeutic targeting with Exenatide. Whilst the project focuses on IIH, the research has the potential to uncover treatments for other conditions of raised ICP (hydrocephalus, traumatic brain injury and space-flight intracranial hypertension

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health Categories: NEUROLOGICAL
Award Title: Defining the role of Bacillus subtilis exoproteases during biofilm formation
Funder: Wellcome Trust

Abstract: Biofilms are communities of microorganisms that attach to surfaces or interfaces which contain one or multiple species and can be beneficial or detrimental for human health. Biofilm formation is tightly regulated by controlling production of exopolysaccharides and extracellular proteins that combine with components including extracellular DNA and extracellular proteases to form a sticky matrix. I am interested in the role of extracellular proteases during biofilm formation. It has been hypothesized that extracellular proteases might be involved in matrix remodelling, cellular dispersal and/or in food acquisition in poor-nutrient conditions. Using the bacterium Bacillus subtilis, I will use biochemical and proteomics approaches to quantify how abundant and how active the extracellular proteases are during biofilm formation. I will also assess if extracellular proteases can be shared among the population and if they confer a selective advantage in certain nutrient environments. By combining live-cell imaging and mathematical modelling, I will also explore how extracellular proteases influence spatial distribution of mixed populations during biofilm formation. The insights garnered with this study will help to understand how exoproteases support biofilm formation in diverse environments and more globally help us to understand why biofilm can be so persistent.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION
Award Title: Designer biology to live image purine metabolism at single-cell resolution
Funder: Wellcome Trust

Abstract: I recently discovered the function of a previously uncharacterised gene, FAMIN, that is linked to Crohn’s disease, leprosy and arthritis. A multifunctional purine enzyme, FAMIN is the pacesetter for purine recycling and hence determines cellular redox status, pH balance and energy production. Altogether, these control macrophage functions, such as bacterial killing and cytokine production. Importantly, my work has established this therapeutically targetable purine pathway as a direct driver of human inflammatory disease. However, further investigation of this pathway is currently limited by the inability to directly visualise and study purine metabolites in-situ, in real-time, and at single-cell resolution. Thus, the spatiotemporal dynamics of purine metabolism are mostly unknown. Assessing these dynamics will be crucial in understanding how purine dysfunction emerges in individual cells and can influence disease pathogenesis, for example through affecting redox state. Samie Jaffrey has pioneered technology that could overcome this hurdle. His group has generated programmable RNA-biosensors capable of live-imaging metabolites in single cells. I intend to learn these techniques and will engineer bespoke sensors for purine metabolites. I shall use these biosensors to dynamically track purine metabolism, and interrogate how environmental triggers can cause the purine dysfunction seen in numerous pathological contexts including chronic inflammatory diseases.

Lay Abstract: Cells carefully balance how they metabolise nutrients in order to maintain a healthy state, avoid the build-up of toxic chemicals, and to support essential activities such as responding to infection. Conversely, metabolism is frequently altered in disease processes such as cancer and autoimmunity. I am proposing to learn new methods to create sensors that can live-track metabolite levels in individual cells and will utilise it to study a particularly important group of metabolites known as purines. Purines perform several critical functions. For example, they are required as the building blocks for our DNA and as cofactors for the chemical reactions occurring in our cells. I recently discovered a novel role for purine metabolism in controlling inflammation. I will utilise my biosensors, a much needed addition to the metabolism research toolkit, to directly image purine regulation and better understand its role in preventing diseases such as inflammatory arthritis and Crohn’s disease.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Detection and sequencing of SARS-CoV-2 derived HLA-I bound antigenic peptides in the blood of COVID-19 patients: mapping the CD8 T cell response.
Funder: Medical Research Council

Abstract: The role that CD8 cytotoxic T cells play in the clearance of viral infections cells is well established, and depends upon the recognition of short (typically 9-11 mer) antigenic viral peptide epitopes presented on HLA class I molecules (HLA-I). The design of effective future vaccines, that can induce both classical memory B cell antibody, and CD8 T cell responses therefore requires that we identify, map and include the most antigenic epitopes being presented to CD8 T cells. In this study we will take advantage of the presence in serum and plasma of both soluble HLA-I and extracellular vesicles (EV) expressing HLA-I as a source of the cellular immunopeptidome. Based on our existing recent studies that both cancer cell line derived and patient plasma EV HLA-I contain tumour associated antigenic peptides, we hypothesise that COVID-19 induced inflammation in the lungs will release excess soluble and EV HLA-I into plasma which we can utilise as a simple to access liquid biopsy, to immunoisolate the HLA-I, extract the antigenic peptides and de novo sequence by mass spectrometry. By comparison to the known viral proteome we will rapidly identify viral epitopes across a wide range of HLA-I alleles present in the population. We aim to rapidly process up to 200 patients samples to build a comprehensive map of real viral antigenic epitopes of use for future intelligent vaccine design.


Research Activity Codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health Categories: INFECTION
Award Title: Developing Machine Learning Approaches for Survival Analysis and Patient Stratification in Inherited Cardiac Conditions
Funder: Wellcome Trust

Abstract: Inherited Cardiac Conditions (ICCs) include a variety of diseases for which the genetic basis and pathogenesis is still majorly unexplained. The clinical outcomes of patients with ICCs are very diverse, rendering diagnosis, prognosis, and accurate therapeutic decisions very challenging. The purpose of this project is to develop machine learning approaches that will be able to explain some of the survival and clinical differences among patients with the same ICC and describe genetic biomarkers responsible. This will enable better patient stratification which will lead to more accurate diagnosis and assessment of therapeutic actions that need to be taken. The modelling approaches will be based on cardiac imaging and genetic data collected from patients across the ICC spectrum and healthy volunteers.


Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: CARDIOVASCULAR
Award Title: Developing a human pluripotent stem cell-based strategy for treating Hirschsprung disease
Funder: Medical Research Council

Abstract: Hirschsprung disease (HSCR) is the consequence of a failure of neural crest-derived enteric neural progenitor cells to colonise the distal gut during embryonic and fetal development. Nevertheless, such progenitors derived from mouse and human postnatal gut have been shown to effectively colonize, and differentiate within, aganglionic gut explants from animal models of HSCR and from affected patients, demonstrating that cell therapy should be a viable option for treatment. However, harvesting sufficient progenitor cells from human gut biopsies poses a significant hurdle which could be overcome by their production from differentiation of human pluripotent stem cells (hPSC). We have established an effective protocol to derive neural crest cells from hPSC in chemically defined, xeno-free conditions, and have shown that these can generate enteric neural progenitors which can colonise long term and efficiently the intestine of animals following transplantation and also produce enteric neurons in vitro. In this project we will establish the preclinical basis for a regenerative medicine approach to treating HSCR by transplantation of hPSC-derived enteric neural progenitors to re-innervate the affected part of the gut. To this end we will assess the ability of our hPSC-derived enteric neuron progenitors to correct for the lack of enteric neurons in both established and novel models of HSCR. We will also identify new specific cell surface markers to improve the isolation of enteric neuron progenitors suitable for transplantation and optimise the protocol for their generation. Finally, we will define the best-performing hPSC cell line for generating such progenitors in order to treat Hirschsprung disease.


Research Activity Codes: 5.2 CELLULAR AND GENE THERAPIES
Health Categories: ORAL AND GASTROINTESTINAL
Award Title: Developing a new class of antibiotics based on efflux resistant 4-oxoquinolizines for multidrug-resistant ESKAPE pathogens
Funder: Medical Research Council

Abstract: Antimicrobial resistance (AMR) is a major concern, with increased levels of multidrug resistance (MDR) in many pathogens, resulting in treatment breakdown in the clinic. The O'Neil report suggested that infections caused by antibiotic resistant bacteria could become the leading cause of mortality worldwide, with up to 10 million deaths per year by 2050. The situation is exacerbated by the very poor pipeline of new antibiotics, especially in the case of high priority pathogens identified as being of critical concern by WHO and others.  In many Gram-negative bacteria, efflux pumps play a significant role in resistance to antibiotics and, simultaneously, the ability of bacteria to develop stable high level resistance through target site modifications. Although the development of stand-alone efflux pump inhibitors, which can be used in conjunction with antibiotics to suppress this response, is an attractive idea, it has not been possible to advance candidates to the clinic. We have taken a different approach, by identifying differential binding sites of inhibitors and substrates to efflux pumps, and generating hybrid molecules where efflux-resistance is a feature of the molecule. Such efflux resistance breaker (ERB) modified antibiotics have significant potential for therapeutic development as stand alone therapies and/or as part of a combination therapy. We have good evidence that these compounds  are effective against Acinetobacter baumannii, and the medicinal chemistry optimisation and validation of the technology will extend the utility to other WHO priority pathogens, for which new antibiotics are urgently required. Data generated in this project will provide a framework for the development of efflux-resistant antibiotics, which are potentially more robust in clinical use. The project will focus on lung infection as the primary indication, aiming to [provide early data to support development of new treatments for hospital and ventilator-associated pneumonia.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: INFECTION