GRIAC defines ‘obstructive airway and pulmonary disease’ in relation to healthy ageing, as its main topic, which is reflected in our mission statement. Research projects have to fit within this research topic, describing the projects in their mutual cohesion. The tuning of projects and development into a program is the responsibility of the programme leaders of GRIAC, in exchange with the Scientific Board of the Institute
Our research is aimed to stretch from bench to bedside and back with feedback loops. Central to the research is the goal to translate fundamental findings into the clinical situation and vice versa, i.e. translational medicine (see figure below).
Translational medical management: from diagnosis to treatment
Clinical research is conducted in different patient groups in comparison with normal control volunteers in order to unravel underlying mechanisms of the diseases (genetics, aetiology, pathogenesis, pathophysiology). Furthermore responses to intervention (mediated by either medical therapy, behavioural counselling, rehabilitation or other treatment modalities) as well as parameters of progression of disease are being assessed in relation to the underlying mechanisms of the disease.
Questions that are generated, but unanswered by clinical research, are approached using in vitro cellular systems and in vivo animal models. The other way around, hypotheses generated from in vitro or in vivo research are translated to the general and clinical human situation.
To this aim GRIAC focuses on the following main topics related to obstructive airway and pulmonary disease:
- Identification of risk factors for development, progression and remission of disease
- Identification of disease related genes and their functionality
- Unravelling the pathophysiology of allergen-, environment- and smoke- induced disease, in both humans and animal models
- Unravelling the effects of disease related inflammation on lung function, hyperresponsiveness and remodelling of large and small airways
- Defining new targets for intervention and evaluation of intervention strategies
- Development of non- or minor invasive tools to assess severity of disease and (side) effects of treatment.
Research focus areas
The focus of research is on asthma and COPD, which involves the sub-programmes:
- Epidemiology: Epidemiological studies on endogenous, environmental and lifestyle risk factors, both in general and patient-based populations, from prenatal onwards to old age.
- Genomics: Studies on genes, epigenetics, gene expression and function, molecular mechanisms and gene-gene and gene-environment interactions in disease development, progression, remission, and severity, as well as disease intervention (pharmaco- genomics).
- Pathophysiology and pathogenesis of allergen, smoking and other lifestyle factors, and environment-induced diseases: In vivo studies in humans and animal models using mice and unrestrained guinea pigs. Investigations include lung function techniques and studies of blood, tissues and/or cells derived from airways or lungs. Furthermore, in vitro studies assess cellular activation and interaction as well as signaling pathways in cells and tissue explants (e.g. lymphocyte subsets, epithelial cells, fibroblasts, intact airway, and smooth muscle preparations). Interactions of different cell types are studied in cells obtained by sputum induction as well as airway and lung tissue obtained by bronchoscopy, by surgical biopsy or autopsy. The Placebo controlled food provocation database provides an excellent method to investigate the allergic response to foods.
- Assessment, modulation and intervention in disease severity, progression and remission: Disease outcome assessment is being studied with techniques such as exhaled breath analyses and small airway function. In addition, validated questionnaires on Quality of Life, drug side effects, hyperresponsiveness and symptoms are developed for diagnostic purposes as well as outcome assessment. Interventions can be at the level of cell cultures, animal models and clinical studies with targeted therapy.
The main strategies to reach our goals are discussed below:
The availability of genetic techniques and the collaboration with the Department of Genetics (Head: Prof. C. Wijmenga) have greatly extended the genetic sub-programs, allowing genome-wide association and methylation studies, high throughput genetic SNP detection, fine-mapping in relevant chromosomal regions and candidate gene studies. Deep sequencing techniques and analysis strategies are currently being developed.
Since gene-environment interactions are important for understanding complex diseases like asthma and COPD, these have been explored in several sub-programs, in collaboration with multiple groups in the Netherlands and abroad. This has resulted in gene-environment interaction studies on atopy and asthma, and on COPD onset and progression. The GRIAC group collaborates internationally and takes the lead in some EC-funded FP7 projects (allergy and asthma: MeDALL; COPD: COPACETIC) on genetics and epigenetics of asthma and COPD, and in exploration of specific gene-environment interactions in these projects. The exposome concept refers to the totality of environmental exposures from conception onwards, and is a novel approach to studying the role of the environment in the development of lung disease in the Lifelines cohort. Furthermore, GRIAC is leading studies on gene expression profiling (transcriptomics) and collaborates internationally (University of British Columbia, Laval University) on studies linking gene expression to (epi)genetic variants (eQTL analysis).
Proteomic and lipidomic research has added important possibilities to develop disease susceptibility markers and disease progression and intervention tools. To enable clinical studies that require greater power, continuing and promoting collaboration with general hospitals in the region has expanded the recruitment population. To enhance the quality of the collaboration, local physicians in these hospitals are more involved in the research group and also propose their own studies for discussion in research meetings.
GRIAC is actively engaged in studies linking clinical outcomes to (molecular) pathophysiology. Often inspired by outcomes from omics studies, the functionality of genes and proteins in disease is studied using molecular approaches in cells and tissues from patients, in cell lines and in animal models. Molecular techniques are being used more effectively and widely, and are being introduced when not present (either in our own labs or as part of local facilities; for example, the recently developed custom micro-array development and accompanying data-mining). In vivo and in vitro silencing of genes are now established techniques that are operational at the University Medical Center and Pharmacy, including the development of knock out and transgenic mouse models. This has enabled the use of RNAi and pharmacological modulation of membrane and nuclear receptors and signaling proteins in cells and tissue slices. Fundamental to this line of research is the exploration of intracellular pathways relevant for disease development.
Patient centered research is at the heart of GRIAC. Our translational research approach included clinical and intervention studies in asthma and COPD. Moreover, several cohort studies, both regional as well as national, are lead by GRIAC investigators. The LifeLines cohort study is a unique asset for large scale epidemiological research into healthy ageing.