NIHRDataInsights/HRCSData huggingface dataset:
Title: The development of superior LTA4H modulators for treatment of allergic airway disease
Funder: Asthma UK

Abstract: <p>The pro-inflammatory lipid mediator leukotriene B<sub>4</sub> (LTB<sub>4</sub>) is implicated in the development of allergic airway inflammation. Accordingly, there has been a significant pharmaceutical effort to reduce LTB<sub>4</sub> levels in asthma through the generation of selective inhibitors that target the enzyme that regulates the rate limiting step in its synthesis &ndash; leukotriene A4 hydrolase (LTA<sub>4</sub>H). Though LTA<sub>4</sub>H is classically a pro-inflammatory enzyme that catalyzes the intracellular synthesis of LTB<sub>4</sub>, we have recently identified a novel extracellular anti-inflammatory activity for the same enzyme in degrading the neutrophil chemoattractant Proline-Glycine-Proline (PGP). PGP is generated from extracellular matrix collagen by the action of neutrophil derived proteases, and a failure to degrade this peptide can result in a self-sustaining vicious circle of neutrophilic inflammation, as seen in patients with chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Thus LTA<sub>4</sub>H possesses important opposing pro- and anti-inflammatory activities that must be taken into account when considering therapeutic intervention. We have demonstrated that conventional LTA<sub>4</sub>H inhibitors fail to distinguish between the two activities of LTA<sub>4</sub>H and thus may inadvertently prevent PGP degradation with potentially dangerous consequences. Indeed, we show that mice lacking LTA<sub>4</sub>H actually display PGP accumulation and greater airway hyperreactivity in our physiologically relevant pre-clinical model of allergic airway disease. There is therefore, the urgent need to develop novel LTA<sub>4</sub>H modulators that distinguish between the two opposing activities by preventing LTB<sub>4 </sub>generation whilst maintaining PGP degradation. We have developed a series of such compounds that exhibit potent inhibition of LTB<sub>4</sub> production in a whole blood assay whilst leaving the PGP degrading activity unscathed. This proposal seeks to validate the risk of global LTA<sub>4</sub>H inhibition in the treatment of allergic airway disease and develop our exciting findings to obtain proof of concept that our novel LTA<sub>4</sub>H modulators confer superior protection than conventional inhibitors in a pre-clinical animal model. The proposed work is critical to the development of our current studies to a clinical setting.</p>


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM
Title: Generation of Small Molecule Asthma Disease Modifying Agents from a TB Derived Peptide Lead
Funder: Innovate UK

Abstract: Peptinnovate is a drug discovery and development company based in the Stevenage Bioscience Catalyst on the GSK site. The company's core research is based on molecules derived from Mycobacterium tuberculosis proteins as innovative immunomodulatory agents for the treatment of chronic inflammatory diseases. The lead molecule PIN201104 is an extremely safe, low molecular weight peptide identified by phenotypic drug discovery in collaboration with a number of leading UK academic groups. PIN201104 is being progressed into the clinic as a first in class disease modifying agent for the treatment of asthma and other chronic inflammatory conditions. Peptinnovate through this grant will exploit the disease modifying approach it has identified for PIN201104 to generate small molecule analogues. Further modification of these analogues subsequent to this project will allow the generation of orally active disease modifying agents for the treatment of mild to moderate asthmatics. There are currently no disease modifying agents available for the treatment of asthma. Peptinnovate is pioneering the discovery of agents with the potential to change the underlying disease of chronic inflammatory asthma and lead to potential curative therapies.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM
Title: Neuro-immune-stromal pathways sense environmental change to regulate repair versus remodelling during airway disease
Funder: Wellcome Trust

Abstract: This application will test the hypothesis that pulmonary immune homeostasis is maintained by a network of tissue resident cells that continually monitor environmental change. Disruption of local neuro-immune-stromal interactions either by genetic or environmental factors, alters the threshold for immune responses to usually innocuous particles such as dust, pollen or dander leading to chronic airway inflammation and tissue remodelling. I will ascertain the cellular and molecular composition of the airway wall parenchyma in children and adults with severe asthma and use machine learning tools and mouse models to determine the impact on lung function. Viral infection and pollution are common triggers for asthma severity, and I will establish how the immune/stromal niche communicates with the external environment to react to these inhaled stimuli, focussing on interaction with neuronal systems. I will examine how these interactions differ in severe asthma and contribute to the ensuing inflammation, remodelling and lung dysfunction. I will investigate the cellular interactions between fibroblasts, extracellular matrix and type 2 immune cells that facilitate repair versus remodelling during severe asthma. Ultimately this programme will reveal insight into mechanisms underlying tissue remodelling versus repair during severe asthma.

Lay abstract: Inflammation is the body’s response to harmful stimuli and is followed by a phase of repair to restore normal organ function. Sometimes this beneficial repair process develops into a harmful process called tissue remodelling that may limit the normal function of that organ. Severe asthma is complicated by airway remodelling, even in young children, but we don’t understand the mechanisms that trigger this harmful aspect of severe disease. I will perform an in-depth analysis of the cells and molecules that are present in airway wall biopsies from children and adults with severe asthma and determine how their interactions impact lung function. I will assess communication networks between immune cells and resident lung cells called fibroblasts and examine how their interactions are affected by factors, such as pollutants and viruses, that are inhaled when we breathe. This project will increase our understanding of airway remodelling and facilitate development of new treatments.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM
Title: Resolution of inflammation in the human lung: Mechanisms involved in leukocyte egression across the alveolar and bronchial epithelium.
Funder: Medical Research Council

Abstract: During resolution of lung inflammatory diseases, leukocytes can leave the lung interstitium across the epithelial barrier passing into the airways or alveolar air-space. This is termed 'transepithelial migration' or 'egression'. Egression across the bronchial epithelium allows leuckoytes to be cleared on the mucociliary escalator; in contrast egression across the alveolar epithelium may interfere with alveolar gas exchange. We have shown that the integrin LFA-1 interacting with its ligands ICAM-1 and ICAM-2 on the epithelium is required for egression across the bronchial epithelium but nothing is known of migration across the alveolar epithelium. As well as the importance of adhesion molecules, other factors play a role in regulation of egression. We are interested particularly in the highly evolutionary conserved Slit/Robo family of neuronal guidance molecules that are expressed at high level in the brain and the lung and to a lesser extent in all other organs. There is a gradient of Slit2 in the lung (produced by bronchial epithelial cells; BECs) with high levels in the bronchial airspace, but with little or no Slit2 in the alveolar air space . We have shown effects of hSlit2/Robo signalling both on epithelial cell adhesion and junctional stability and on leukocyte chemotaxis and polarisation. Based on (a) differences in expression of the integrin ligands ICAM-1 and ICAM-2 in bronchial and alveolar epithelium (b) the evidence for differential expression of Slit2/Robo1 between the alveolar and bronchial epithelium (3) The ability of Slit/Robo to alter integrin activity, with effects on BEC and leukocytes; We propose that differential expression and regulation of key adhesion molecules such as ICAM-1 and ICAM-2 together with cytoskeletal modulators such as Slit2/Robo1 act to confine and localise sites of leukocyte-epithelial interactions to promote resolution of inflammation and our project will address this hypothesis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM
Title: Pericyte mobilisation and functional plasticity in chronic allergic airway disease
Funder: Medical Research Council

Abstract: Aim 1: To investigate the contribution of pericyte recruitment to airway hyperreactivity. The kinetics of pericyte mobilisation to the airway smooth muscle and the therapeutic benefits of enhancing PDGF signalling in the lung vasculature in the context of chronic allergic airway inflammation will be investigated through the use of adenoviral-vector mediated overexpression of PDGF-B in the HDM model of asthma. The experimental techniques involved in this part of the project include intranasal administration of saline and HDM extract, tail vein injections of adenovirus vectors, euthanasia and dissection of experimental animals, preparation and immunofluorescent staining of mouse tracheas and lung sections, confocal microscopy, image analysis and performing lung function measurements using the FlexiVent system. Aim 2: To identify factors that drive the mobilisation of lung microvascular pericytes to the airway wall in a mouse model of allergic asthma. This part of the project will provide mechanistic insight into pericyte mobilisation and migration in allergic airway disease. The experimental techniques involved in this part of the project include intranasal administration of saline and HDM extract, euthanasia and dissection of experimental animals, lung cell isolation, fluorescence-activated cell sorting, modified Boyden chamber assays and ELISA. Aim 3: To investigate the ability of pericytes to differentiate into smooth muscle in the context of allergic inflammation. This part of the project will characterise the progenitor cell characteristics of lung pericytes. The experimental techniques involved in this part of the project include intranasal administration of saline and HDM extract, euthanasia and dissection of experimental animals, fluorescence-activated cell sorting, in vitro differentiation assays and cell contraction assays.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM
Title: ADI 1.02: Development of topically acting Allergen Delivery Inhibitors as novel treatments and prophylactics for allergy.
Funder: Wellcome Trust

Abstract: Our aim is to develop a new class of drugs, Allergen Delivery Inhibitors (ADIs), for the treatment and prevention of allergic diseases, especially asthma. The next 30 month stage will produce a topically active candidate drug. An early out-licence point then exists or, alternatively, success will stimulate follow-on investment for us to progress towards the initiation of clinical studies. The starting point is a group of compounds which in animal models prevent allergy development, and which block the effects of allergen challenge when allergy is already established. The science background is: House dust mites (HDM) are major causes of allergy. A family of cysteine peptidases are their most important allergens. These peptidases: 1) Are highly allergenic. 2) Open epithelial tight junctions giving all allergens access to antigen presenting cells. 3) Activate signalling events that promote allergy. No medicines target these steps, but ADIs reduce these critical events, thereby preventing and treating allergy. Proof of principle studies show that inhibition of the key peptidase protects against other, non-enzymatic, allergens in vivo. Differences between HDM peptidases and human orthologues make specific inhibitionfeasible. Conversely, the enzymes from different types of dust mite are highly conserved, so one inhibitor should be effective in all cases.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM
Title: The opposing roles of leukotriene A4 hydrolase (LTA4H) in governing pulmonary neutrophilic inflammation.
Funder: Wellcome Trust

Abstract: When bacteria enter our lungs, our immune system fights back to neutralise any danger. One of the immune system s key 'soldiers' is a cell known as a neutrophil, which rushes to the site of infection and kills the bacteria. However neutrophils can also cause collateral damage to surrounding lung tissue, and so neutrophils need to act swiftly and then leave the site of infection. Consequently, neutrophil persistence contributes to the development of chronic lung diseases. I have identified a no vel anti-inflammatory role for an enzyme in degrading a signal which causes neutrophils to persist in the lung. However, I hypothesise that cigarette smoke can inhibit this anti-inflammatory role of this enzyme leading to neutrophil persistence and lung damage. Furthermore, this enzyme also has an opposing pro-inflammatory role that generates another signal which drives neutrophils into the lungs. There is currently significant interest in developing drugs to inhibit this pro-inflammatory activi ty of this enzyme to alleviate neutrophil-mediated damage in many diseases. However, these inhibitors may inadvertently inhibit the novel anti-inflammatory role and promote neutrophil-mediated damage. I will examine the specific functions of this enzyme and design more specific therapeutics that only target one of its actions.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM
Title: The Consequences of Neonatal Respiratory Virus Infection for Pulmonary Innate Immunity
Funder: Medical Research Council

Abstract: Respiratory Syncytial Virus is the major cause of bronchiolitis in infants. Bronchiolitis is associated with the development of wheezing and asthma in childhood. Recent studies have found that prevention of RSV infection in neonates by monoclonal antibody prophylaxis, reduces the incidence of wheezing and asthma later in life, suggesting a causal link. The objectives of this proposal are to understand how neonatal Respiratory Syncytial Virus (RSV) infection leads to increased inflammation in the lungs later in life, using a murine model. Mice infected with RSV as neonates develop exacerbated inflammatory responses to RSV re-infection, but remarkably, also to influenza infection and airway challenge with LPS. This has lead to the hypothesis, which will be tested in this project, that neonatal RSV infection leads to a long-term pro-inflammatory alteration in innate immune responses in the lungs. The broad experimental aim of this project is to understand how neonatal RSV infection leads to exacerbated inflammatory responses during later-life challenge to the lungs. Mice will be infected with RSV as neonates and the long-term effects of RSV infection determined at 6 weeks of age. The first experimental aim of this project will establish the impact of neonatal RSV infection on different types of airway inflammation later in life, to determine whether RSV infection selectively promotes or biases the inflammatory response. Th1- and Th2- driven pulmonary inflammation and inflammation in response to house dust mite extract and TLR agonists, will be tested. In all models, the extent and nature of airway inflammation will be determined by flow cytometric analysis of cellular infiltration, measurement of cytokines in bronchioalveolar lavage fluid and measurement of airway function by plethysmography. Airway macrophages and the respiratory epithelium detect pathogens, alert the immune response and control the nature and extent of airway inflammation. The second aim of this project will test the hypothesis that there is altered function and phenotype of lung macrophages and respiratory epithelial cells following neonatal RSV infection. Cell phenotype will be determined by flow cytometry, inflammatory cytokine production will be measured ex-vivo, and epithelial barrier function measured in vivo and ex vivo. The third aim of this project is to use whole mouse genome microarrays to reveal long term changes in gene expression in the lungs following neonatal RSV infection and whole genome methylation analysis to identify epigenetic changes in lung cells, which may mediate long term alteration in pulmonary immunity. This work will identify the long-term changes in the immune environment in the lungs caused by neonatal respiratory infection and identify potential mechanisms for the development of childhood asthma following bronchiolitis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Regulation of neutrophilic inflammation by the HIF/PHD pathway.
Funder: Wellcome Trust

Abstract: White blood cells are critical for our lung defences against infections, but if they remain in the lung they cause lung damage in common and serious lung conditions including chronic obstructive pulmonary disease (COPD) and bronchiectasis. Neutrophils are one of the first white blood cells to reach these areas, but it is their removal that is critical in preventing this damage. This removal occurs in part though their ability to die in a programmed manner, a process regulated by oxygen availab ility. We now know this process is controlled by a pathway that enables cells to detect and respond to changes in oxygen tension, the HIF/PHD pathway. This pathway is also tightly linked to the energy status of cells. Relatively little is currently known about the interaction between energy status and neutrophil survival. We propose to investigate whether the HIF/PHD pathway can directly regulate the ability of neutrophils to generate energy, protect themselves from damaging stresses and kill bacteria through changes in their metabolism using neutrophils isolated from mice lacking key members of the HIF/PHD pathways, healthy volunteers and patients with COPD and bronchiectasis. In the longer term we hope these insights will allow development of novel treatments for these diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Role of ATP in Chronic Cough
Funder: Wellcome Trust

Abstract: The cough reflex is triggered by ion channels present on vagal nerve termini which can be activated by a wide variety of irritants. Utilising a P2X3 antagonist we have identified ATP as a driver of chronic idiopathic cough which is treatment refractory. However, the mechanisms are not known and it is not clear whether similar efficacy will be observed in chronic cough associated with common respiratory diseases. We have identified different neurophenotypes in patients with chronic cough associated with different lung diseases suggesting that a single therapeutic may not address cough across all indications and that mechanistic information will be required. Furthermore, upstream targets, involved in the release of ATP, may provide a broader efficacy profile as ATP has been shown to have a range of disease relevant biological effects in the lung mediated by purinoceptors. We will identify (1) whether ATP is a biomarker of treament sensitivity; (2) upstream targets involved in the release of ATP; (3) the contribution of the upper airway to ATP-induced sensations; (4) the role of ATP in mediating chronic cough across other airway diseases? This project will identify novel targets, biomarkers and the patient phenotypes that will respond to treatment.

Lay abstract: Cough is the most common condition for which patients see their doctors, but currently there are very few treatments that improve cough. Coughing occurs when airway nerves are activated; irritating chemicals in the air, changes in temperature and choking on food can all cause coughing in this way. In many people with chronic coughing we think the nerves controlling cough are over-active and this may be caused by a chemical in the airways known as ATP. This idea comes from recent studies showing that a treatment that blocks the effect of ATP on nerves improved cough by 75% in chronic cough of unknown cause. Not everyone responded to the treatment though, and we don’t know whether this new treatment might work in all types of cough, such as in asthma, smoking related lung conditions, lung fibrosis or other lung diseases. Our research aims to 1. understand more about why this new treatment works in some people 2. develop tests that would tell a doctor which patients and which types of coughs might respond best to new treatments, 3. work out what sort of other new treatments might help to treat cough and other symtpoms due to ATP or over-active airway nerves.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;NEUROLOGICAL
Title: The Role of GABAB Receptor Mechanisms in Chronic Cough
Funder: Medical Research Council

Abstract: Cough is the most common symptom for which patients seek medical care. Chronic cough (>8weeks) is reported by 14-23% of the population and has a substantial impact on quality of life. Remarkably little is understood about the mechanisms involved in the human cough reflex. Gastro-oesophageal reflux disease is thought to be a major cause of chronic cough but evidence suggests acid suppressing therapies such as proton pump inhibitors are ineffective. We have developed a validated, semi-automated ambulatory monitoring system, which objectively identifies the precise timing and frequency of coughing episodes. Combining this method with oesophageal pH/impedance monitoring, we have shown that in almost 50% of chronic cough patients, cough follows reflux events more often than expected by chance alone, and irrespective of the acidity of the refluxate. The main mechanism underlying gastro-oesophageal reflux events is transient lower oesophageal sphincter relaxation (tLOSR). Gamma-aminobutyric acid type B (GABAB) receptor agonists such as Baclofen inhibit tLOSRs and consequently reflux events by up to 40%. Baclofen also inhibits cough responses to inhaled capsaicin in healthy controls and subjectively improves treatment resistant chronic cough, but longterm therapy is poorly tolerated due to CNS side effects and acute withdrawal can result in seizures. We hypothesise that Lesogaberan, a novel mainly peripherally acting GABAB receptor agonist will inhibit human cough (without CNS side effects) via two mechanisms i) a direct inhibitory effect on afferent pathways responsible for evoking cough and ii) an indirect effect via reduction in tLOSRs and reflux events in patients where reflux is temporally linked to cough. We therefore propose two studies to investigate the effect of Lesogaberan i) on cough reflex sensitivity in healthy controls and ii) on objective cough frequency in chronic cough patients with and without cough triggered by reflux events.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY;ORAL AND GASTROINTESTINAL