Loss of tissue homoeostasis in asthma

Project description

Asthma is characterised by airway hyper-responsiveness, chronic inflammation and remodelling. Airway narrowing during an asthmatic attack is caused by rapid and excessive contraction of airway smooth muscle (ASM) cells lining the conducting airways. Over longer periods (months or years), repeated episodes of intense inflammation cause ASM proliferation leading to marked thickening (or remodelling) of the airway wall. While each of these three features contributes to asthma severity, how they interact is poorly understood. Most importantly, it is not clear whether airway hyperresponsiveness or remodelling are causes or consequences of the disease.

We hypothesize that while airway remodelling is initiated by inflammatory mediators, it is perpetuated by mechanical factors. We know that cells respond to their physical environment through mechanotransduction, the translation of mechanical forces into biochemical signals. The cell changes that arise from this can lead to an altered cell microenvironment, creating a developmental feedback. Interplay between such mechanosentive pathways and other inter- and intra-cellular signalling mechanisms are therefore potentially responsible for maintaning a health airway. In this project we will use extensive data from a mouse model of asthma to develop computational biomechanial models of airway tissue combined with regulatory biochemical signalling to establish a mathematical description for the homoeostatic state (ie for healthy airways). This will then allow us to understand how perturbations to this homoeostatic state could drive airways into an asthmatic state, and ultimately to understand which processes are the cause of the disease.