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Karolinska institutet
Karolinska universitetssjukhuset
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Åsa Wheelock Group

About

Our research program can be broadly defined as developing a respiratory
systems biology approach utilizing a range of ‘omics, bioinformatics, &
statistical platforms to characterize molecular sub-phenotypes of chronic
inflammatory lung diseases. We focus equal efforts on translational studies
of the response to environmental exposures in patients with COPD and asthma,
and innovation & methodology development in the fields of intact quantitative
proteomics, multivariate modeling and data integration. Our translational
systems medicine studies encompass profiling of mRNA, miRNA, proteomes,
metabolomes and lipid mediators of from multiple lung compartments (airway
epithelium, alveolar macrophages, exosomes, and bronchoalveolar exudates)
using multiple omics platforms, in combination with extensive clinical
phenotyping. The strength of our approaches is the ability to integrate
information from multiple molecular levels, including the mRNA, miRNA,
protein and metabolite levels, with rigorous clinical characterizations in
order to understand disease mechanisms on a systems level.
The true power – and challenge – in these studies are the integration of
the multi-molecular level screening results with in depth clinical
characterizations in order to understand and categorize unknown
sub-phenotypes of complex disease. Like many other complex diseases, both
COPD and asthma represent umbrella diagnoses encompassing a range of
underlying molecular mechanisms which all lead to a similar set of symptoms
or alterations in lung function. However, the reliance on symptoms and
alterations in lung function for diagnosis makes it challenging to develop
diagnostic and treatment options that are efficacious across the different
subgroups of patients. Molecular sub-phenotyping thus represents an essential
step towards the discovery of relevant diagnostic or prognostic biomarkers
and treatment options for specific patient groups, a.k.a. personalized
medicine.

In the Karolinska COSMIC study, we are investigating molecular sub-phenotypes
of smoking-induced COPD. A particular focus relates to recent epidemiological
indications of gender differences in both incidence and severity of disease,
with post-menopausal women being at greatest risk. The study encompasses
profiling of mRNA, miRNA, proteomes, metabolomes and lipid mediators of from
multiple lung compartments (airway epithelium, alveolar macrophages,
exosomes, and bronchoalveolar exudates) using multiple omics platforms, in
combination with extensive clinical phenotyping of early stage COPD patients,
never-smokers, and smokers with normal lung function from both genders. The
completion of the first leg of the study revealed significant differences in
the macrophage proteome between COPD patients and healthy controls. These
differences were entirely driven by the female population, with a subset of
19 protein biomarkers providing highly significant classification of healthy
smokers from early stage COPD patients (p=10-7), with 78% predictive power
(Kohler et al., JACI, 2013). These alterations in the proteome of women could
be linked to specific molecular pathways related to macro-autophagy which has
been associated with an airway inflammatory phenotype, thus linking our
molecular results to know gender-differences in clinical phenotypes. Results
from both up-stream screening of mRNA and miRNA, and down-stream screening of
lipid mediator and cytokines support the existence of gender-associated
molecular sub-phenotypes of COPD. By using unbiased clustering based on
identified ‘omics-based COPD classifications, we can identify a sub-group
of subjects among smokers with normal lung function being at elevated risk of
developing COPD. This illustrates part of the beauty and vision of systems
medicine; To provide prognostic molecular insight into deviations from the
healthy state, rather than the traditional definitions of disease states.
In the SUBWAY study, we have investigated the molecular responses to subway
air exposure in asthmatic subjects compared to healthy. Subway air contains
high levels of particulate matter enriched in iron oxides, which can cause
oxidative stress and subsequent release of pro-inflammatory mediators in the
airway. The human subjects in this study, all naïve to previous subway
exposure, were sampled through bronchoalveolar lavage (BAL) both pre- and
post subway exposure to normalize for inter-individual variability. We
employed a combination of miRNA profiling of exosomes (Levänen et al, JACI,
2013) and lipid mediator profiling (Lundström et al, PLoS One, 2011) from
BAL fluid. The results showed that subjects with mild asthma have an impaired
ability to down-regulate the initial inflammatory response towards subway air
exposure, indicating a prolonged and intensified initial inflammatory
reaction in asthmatics that is quickly resolved in healthy subjects.
Interestingly, we also found alterations in both lipid- and miRNA profile at
baseline levels in asthmatics compared to healthy, indicating a
predisposition to an adverse response even in mild intermittent, stable
asthma.

In the LUNAPRE study, we are using our systems medicine workflow to
investigating an emerging and steadily growing subgroup of patients at
elevated risk of developing early onset obstructive lung disease; survivors
of bronchopulmonary dysplasia (BPD). Inflammatory conditions occurring in
childhood and adolescence of very prematurely born children due to oxygen
treatment and/or developmental impairments during the neonatal period often
leads to obstructive disease, airway hyperreactivity, and premature decline
in lung function in early adulthood. Currently this type of obstructive
disease is categorized under the umbrella diagnosis COPD due to the
associated symptoms and lung function impairments. However, due to the
differences in etiology compared to other forms of COPD, the underlying
mechanisms are likely to be distinct from e.g. smoking-induced COPD.
Multi-level molecular characterization of the alterations in the lungs of BPD
patients compared to relevant control groups may reveal subsets of mediators
as well as molecular pathways that are critical in the pathological changes
occurring in BPD- and premature birth-related obstructive lung disease.

Grants

Public outreach and news

2021-11-16 08:51

The Swedish Research Council grants 14 research projects at KI for their research about postcovid. A total of SEK 50 million is granted, of which SEK 33,800,000 is awarded to nine…

2021-05-07 16:20

Thirteen KI researchers have received funding from the Heart-Lung Foundation for their research on the new coronavirus. The grants total SEK 6.5 million, with approximately 40 per…

2019-06-20 10:00

KI-researcher Åsa Wheelock has been awarded a grant of SEK 15 million for molecular research on chronic obstructive pulmonary disease.

Group leader

Åsa Wheelock, principal researcher, docent, asa.wheelock@ki.se

Selected publications

About CMM

The Center for Molecular Medicine (CMM) is a foundation instituted by the Stockholm County Council (Region Stockholm). CMM is at the heart of a close partnership with the Karolinska University Hospital and Karolinska Institutet, fueling advancements in biomedical and clinical research.

Contact

Center for Molecular Medicine Foundation, org. nr. 815201-3689

Karolinska University Hospital L8:05

Visionsgatan 18

171 76 Stockholm, Sweden

communication@cmm.se

CMM
Karolinska institutet
Karolinska universitetssjukhuset