Role of microRNA Regulatory Networks for Leukotriene Modifier Response in Asthma
Amber Dahlin,
Instructor of Medicine and Associate Epidemiologist, Channing Division of Network Medicine,
Brigham and Women’s Hospital and Harvard Medical School
Asthma is a major global public health burden, and severe asthma
subtypes such as aspirin-exacerbated respiratory disease (AERD),
represent a particular treatment challenge. AERD is characterized by
excessive leukotriene (LT) production and end organ hyper-reactivity to
cysteinyl LTs following aspirin ingestion. As a result, these patients
may ideally benefit from leukotriene modifiers (LTMs) such as
montelukast that block LT receptors to relieve symptoms. However,
substantial inter-individual variability in montelukast response exists,
which is partly due to genetic variation in LT regulatory pathways,
resulting in unpredictable therapeutic outcomes. The activity of
microRNAs also influences disease pathogenesis and treatment, as
microRNAs have key roles in regulating gene expression. Interactions
between genes and microRNAs are complex, since multiple microRNAs can
regulate multiple genes and genes can be regulated by multiple miRNAs.
These interactions can be explored computationally by integrating gene
and microRNA expression data to construct networks of correlated
microRNA-gene pairs (i.e. regulatory networks). Rather than analyzing
microRNA-gene pairs separately, this approach enables analysis of
multiple genes and microRNAs simultaneously. Using this approach to
understand how AERD patients may respond to medication can promote
development of personalized therapies, and obtaining insight into
biological pathways will ultimately inspire development of more
effective treatment regimens.
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