Mother project

The first P4O2 project is called the 'mother project'. The project officially started in December 2020.

The objectives were:
1) Identifying the population at highest risk of developing lung disease because of personal factors and environmental exposure so that research can be carried out on mechanisms underpinning the increased risk and potential interventional strategies
2) Improving the ability to characterize environmental exposures and their impact enabling the incorporation of the effects of environment into mechanistic and clinical conceptions of the development of lung disease leading to new interventional strategies
3) Gain insight on the abnormal repair responses to environmental exposures and the interaction with other organ systems to help identify interventional strategies that address derangements that put individuals at risk for developing lung disease on a more systemic level
4) Develop a translational research ecosystem for identifying, conceiving, and testing interventions aimed at preventing the development of lung disease

The project was divided into 12 workpackages:

WP1 - Defining populations at high risk for respiratory disease in the Netherlands, combining risk factors and the external exposome.
WP2 - Identifying gene candidates and pathways involved in to the onset and progression of COPD in existing cohorts.
WP3 - Setting up novel 3D lab-on-a-chip culture models for tissue damage and repair using in vitro models.
WP4 - Building the PARASOL (Prevention of And Risk fActorS for chronic diseases: an Observational study in North HoLland)-cohort for detection of early lung damage.
WP5 - Analyzing the exposome in the PARASOL cohort.
WP6 - Multi-omics in the PARASOL cohort for the detection of biomarkers and potential treatable targets of sub-clinical lung disease.
WP7 - Imaging of the lungs, extra-pulmonary tissue and body composition in the PARASOL cohort.
WP8 - Combining exposome, multi-omic, and imaging data using artificial intelligence to identify phenotypes of groups at-risk for developing lung diseases.
WP9 - Personalized life style interventions and modulation of the metabolic milieu in the PRIL cohort.
WP10 - Mechanistic studies using advanced models to obtain novel insights in lung repair defects that drive lung disease and are influenced by extra-pulmonary tissue.
WP11 - Local and systemic intervention studies to stimulate tissue repair and prevent lung disease.
WP12 - Initiatives to involve stakeholders and disseminate findings.

The project has delivered insight into risk of developing lung disease, cohorts, models, strong multidisciplinary collaboration and a strong foundation to study early development of lung diseases.

We conclude that the risk of developing lung disease is higher when persons are exposed to a high concentration of air pollution, smoke, have a family history of lung disease or have a low SES (PMID: 37137510). The risk factors for lung disease overlap with those of cardio-metabolic diseases, providing the rationale to team up with the Hoorn studies on cardio-metabolic diseases.

In the COPD cohort, we conclude that the generated data led to first insights on gene candidates and pathways involved in the onset and progression of COPD and advanced understanding of COPD pathologic mechanisms which enable biomarker discovery. Also in vitro, we identified candidate genes and signaling pathways involved in the onset of lung disease upon smoking.

For the PARASOL cohort that was impacted by delay in MRB approval, we can conclude that there is a group of healthy volunteers that fitted the inclusion criteria for the cohort, and that was willing to participate in the study with relatively long assessments and multiple home visits. In our population, about 2% showed signs of lung damage on the CT scans (that otherwise would probably not have been detected) and first analyses show that ~85% of the persons had a lung function that would be considered normal. Microbiome and transcriptome data is available and is being analysed at the moment. Besides the aim to study onset and prevention of lung diseases in this cohort, the cohort was also designed to serve as a healthy control population. The cohort has already been used to compare findings in the P4O2 Long COVID cohort, showing that patients in the P4O2 Long COVID study had increased inflammatory markers, reduced renal function, and a different breath profile compared to healthy individuals in the PARASOL cohort (articles under review/in preparation).

During the project we have started the ILD cohort; inclusions have started.

From the exposome work we have learned that it is feasible to measure exposome in a population without lung complaints and that they are very willing to participate, even with 3 home visits at 2 time points. Also, we concluded that those home measurements add information to exposome data that is available on postal code.

From the lifestyle intervention work in PARASOL, we conclude that it is possible to conduct the intervention in this study, that persons are willing to work on the lifestyle intervention even without lung complaints, and that GPs are willing to collaborate on the referral. We also learned that whereas one of the criteria to follow the CooL intervention is being overweight or obese, people with a normal weight in the PARASOL study also still are interested and fit other criteria. It could be considered to adjust the CooL criteria, which might attract another group of persons, potentially more willing to work on lifestyle.

From the in vitro work we produced a microfluidic platform that facilitates more innovative, realistic modeling of lung disease for a range of research questions. We conclude that primary airway epithelial cells cultured can be cultured under air- and (microfluidic) medium flow, that stem cells can be used to generate alveoli (lowest part of the lung, where gas exchange takes place) and endothelial cells on chip and to co-culture them together. Also, that model can be used to study damage and repair responses in the lungs. Skeletal muscle chips could be generated and the system to connect the lung and muscle chip (FlexiX) is very successful. In a new air-tight airway on chip, breath collected from cohort participants was compared to isolated cells of the same participant and the compounds they release into the air in this new chip device. The metabolic characteristics of these cells could be reproduced and analysed in the lab. This led to the discovery of a volatile biomarker of COPD that can be developed further into in vitro workflows for further analysis and potential exhaled breath markers for the clinic.

The project was very successful in generating a public-private multidisciplinary collaboration, which is of great importance to identify treatable traits, innovative personalized therapeutic strategies and to move the findings to clinical practice. This has led to the generation of the P4O2 foundation, to continue the efforts.

The findings can be used by scientists and companies in research and development for lung diseases. The well-defined cohorts are very rich information sources for those stakeholders. Also, regulators can use the data to base decisions on exposome exposure or implementation of a lifestyle intervention in the group of people at risk for developing lung disease. Biomarkers and insights on pathways can be used to develop new therapies by large pharmaceutical companies.

Several of our consortium partners and new partners collaborate on the follow up of the project. Firstly, metabolome analyses in PARASOL and in the COPD cohort will still be performed and CT images will be further analysed by imaging companies. Also, inclusion into the PARASOL cohort will continue to 3000 persons after joining the Hoorn studies. In the COPD-PARASOL-ILD project (co-funded by Health~Holland; UMCG, Amsterdam UMC, Utrecht University, Roche, PExA) we will focus on comparing COPD patients with the persons without a lung disease (PARASOL) and the ILD patients with the PARASOL participants, focussing on data that is generated in this project and extending the data collection. The models are further optimized and used by academics and pharmaceutical companies in the CPBT project (Growth fund).

Overall, the project was successful in setting up cohorts and lab models to study early lung disease and greatly stimulated public-private collaboration in the lung field in the Netherlands. Several innovations have been created/improved and will be further valorized (first biomarkers, lab models, FlexiX, stem cell differentiation, RespiQ breath analyzer, TopMD analysis platform).