Innovating Works

MaeBAia

Financiado
Mechanisms of adverse effects of Beta Agonists in Asthma
Beta2 agonists (B2as) such as the short acting salbutamol, used to relieve acute wheeze, and the long acting salmeterol used to control asthma with inhaled steroids (ICS), are almost universally used in asthma. However, there is s... Beta2 agonists (B2as) such as the short acting salbutamol, used to relieve acute wheeze, and the long acting salmeterol used to control asthma with inhaled steroids (ICS), are almost universally used in asthma. However, there is significant concern over morbidity and mortality related to adverse effects, particularly when used without ICS, and/or in excess at exacerbation (mostly caused by rhinovirus [RV] infection). The mechanisms of adverse effects are not understood. This proposal will rock the asthma world by revealing the mechanisms of these adverse effects, thus reducing asthma morbidity and mortality. I discovered that B2as induced, and augmented RV induction (to mimic exacerbation), of the pro-inflammatory mediator IL-6 in bronchial epithelial cells (BECs) in vitro, via a cAMP dependent mechanism. ICS suppressed this induction. Hundreds of asthma-related pro-inflammatory mediators and airway mucins have potential for induction by cAMP, and for suppression by ICS. I hypothesise that adverse effects of B2as are mediated by cAMP-dependent induction of pro-inflammatory mediators/mucins in BECs and macrophages and that ICS protect against induction. I will use RNA-seq to identify all mediators induced by B2as (±RV), and suppressed by ICS, in commercially sourced human BECs and macrophages (Mφ) and in primary BECs and Mφ from 8 mild asthmatics. I will develop qPCR/protein assays for these mediators, to confirm RNA-seq data, and identify mediators to study in vivo. I will study 24 mild asthmatics at baseline, after 14 days inhaled salmeterol and after 14 days inhaled salmeterol/ICS. To mimic B2a overuse at exacerbation, I will study 10 mild asthmatics to investigate the effect of high dose salbutamol. Clinical responses will be comprehensively assessed and airway inflammation will be studied using state of the art methods. It is essential that these studies are executed urgently to inform safest use of current asthma medication, and future drug development programs ver más
30/09/2024
IMPERIAL COLLEGE O...
2M€
Duración del proyecto: 73 meses Fecha Inicio: 2018-07-31
Fecha Fin: 2024-09-30

Línea de financiación: concedida

El organismo H2020 notifico la concesión del proyecto el día 2024-09-30
Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:
ERC-2017-ADG: ERC Advanced Grant
Cerrada hace 7 años
Presupuesto El presupuesto total del proyecto asciende a 2M€
Líder del proyecto
IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND ME... No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico TRL 4-5