Periodic Reporting for period 2 - MecCOPD (Deciphering the role of biomechanics in chronic obstructive pulmonary disease)
Periodo di rendicontazione: 2022-12-01 al 2024-05-31
Chronic obstructive pulmonary disease (COPD) affects millions of people worldwide and causes debilitating and often fatal breathing problems, with few effective treatments available. COPD posits a significant burden on society by causing major expenses to the health care systems and greatly reducing quality of life for many people. Therefore, developing more effective treatment options would benefit individuals and society as a whole. One hurdle for developing more effective treatment options is the common use of animals in COPD research, such as rodents. Rodents do not naturally develop COPD but have to be induced artificially and even then they do not develop key aspects of human COPD, such as airway disease, including inflammation and narrowing. This limits the types of disease mechanisms and treatments that can currently be investigated for drug discovery. In particular, we hypothesize that in order to develop innovative and effective treatment options, we need to understand how COPD affects the airways, as this is where the disease often starts in humans. Therefore, my team develops innovative in vitro models of human airways, such as so called airways-on-chip, small miniature models of human trachea and bronchioles that can be exposed to cigarette smoke and other triggers of COPD. Additionally, airways-on-chip allow us to test the effect of breathing motions and air flow on the airways to investigate if these rhythmic forces are important for health and, conversely, if their lack due to impaired breathing accelerates diseases progression. Our objectives are to identify risk factors of developing COPD, such as certain air pollutants and diet, and to identify protective mechanisms, such as mechanical stimulation and exercise. We aim to understand how these factors act on the airways in order to identify potential diagnostic markers and drug targets for treatment and regeneration.
We conducted three main investigations
1) We identified structural and functional "benchmarks" of healthy human airways and used these to (i) optimize in vitro models of the human airways, (ii) quantify disease progressions in vitro, and (iii) understand the limitations of other research models, such as rodents. For this, we analyzed and compared native human and rat airway tissues.
2) We identified mechanical forces that shape the development, health and function of in vitro models of the human airways. Specifically, using airway-on-chip technology, we tested breathing-like air flow and stretch as well as blood-flow on the maturation and inflammation of in vitro models of the human airways.
3) We developed innovative imaging methodologies to capture more aspects of the development, health and function of in vitro models of the human airways, including the ciliary beat patterns and the mechanical properties of the secreted mucus.
1) We identified structural and functional "benchmarks" of healthy human airways and used these to (i) optimize in vitro models of the human airways, (ii) quantify disease progressions in vitro, and (iii) understand the limitations of other research models, such as rodents. For this, we analyzed and compared native human and rat airway tissues.
2) We identified mechanical forces that shape the development, health and function of in vitro models of the human airways. Specifically, using airway-on-chip technology, we tested breathing-like air flow and stretch as well as blood-flow on the maturation and inflammation of in vitro models of the human airways.
3) We developed innovative imaging methodologies to capture more aspects of the development, health and function of in vitro models of the human airways, including the ciliary beat patterns and the mechanical properties of the secreted mucus.
We achieved the following progress beyond the state of the art:
1) first "map" of mucociliary clearance function in human and rat airways
2) first quantitative benchmarks for assessing how "human-like" a given preclinical airway model is
3) first physics-based understanding of why rodent airways are different from human airways
4) first evidence that mechanical forces play a key role in maintaining and developing human airway physiology
We expect the following additional progress:
1) development of robust optical method for measuring airway mucus viscosity and elasticity in vitro
2) development of physics-based computational models predicting mucociliary clearance function depending on tissue morphology
3) understanding impact of diet on COPD susceptibility
4) understanding impact of mechanical forces on tissue health and COPD progression
5) understanding impact of paracrine signaling on mucociliary clearance in health and in COPD
1) first "map" of mucociliary clearance function in human and rat airways
2) first quantitative benchmarks for assessing how "human-like" a given preclinical airway model is
3) first physics-based understanding of why rodent airways are different from human airways
4) first evidence that mechanical forces play a key role in maintaining and developing human airway physiology
We expect the following additional progress:
1) development of robust optical method for measuring airway mucus viscosity and elasticity in vitro
2) development of physics-based computational models predicting mucociliary clearance function depending on tissue morphology
3) understanding impact of diet on COPD susceptibility
4) understanding impact of mechanical forces on tissue health and COPD progression
5) understanding impact of paracrine signaling on mucociliary clearance in health and in COPD