ADAM33 gene and environment interactions in developing lungs and their involvement in the early life origin of asthma

Lead Research Organisation: University of Southampton
Department Name: Clinical and Experimental Sciences


Asthma is a common disease affecting both adults and children. It causes wheeziness, chest
tightness and cough and is often triggered by exposure to allergens (eg. dust or animal fur). As a
result, the airways contract too much and too easily, limiting airflow into the lung. Asthma tends to
run in families suggesting there are ‘asthma’ genes. ADAM33 is such a gene where small changes
have been found in people with asthma and in young children at risk of asthma. It is found in
specialized airway ‘smooth muscle’ cells (ASMCs) that cause airway ‘twitchiness’ in asthma and it is
released in fluid that is present in the airways of asthmatic patients. In baby lungs, I have found
that ADAM33 occurs in stem cells that give rise to ASMCs. Therefore, the objectives of my research
are to study the role of ADAM33 in airway development and to understand whether release of
ADAM33 can give rise to abnormal ASMC development that might lead to asthma. I will also
investigate whether, and how maternal allergy, a factor that predisposes babies for asthma, affects
ADAM33 in ASMC. These studies should help devise new treatments for asthma close to the origin of
the disease.

Technical Summary

Aims: A Disintegrin And Metalloprotease (ADAM)33 is a susceptibility gene associated with asthma,
bronchial hyperresponsiveness (BHR) and reduced lung function in young children. High levels of a
55 kDa soluble fragment of ADAM33 (sADAM33) have been found in bronchoalveolar lavage fluid
(BALF) of asthmatic subjects where levels correlate with reduced lung function. To investigate the
early life contribution of ADAM33 to asthma pathogenesis, I have found that ADAM33 expression
increases when spontaneous peristaltic contractions of the airways commence in utero and when the
lungs inflate post partum. Using human embryonic lung explants, I have found that recombinant
sADAM33 enhances smooth muscle development, identifying a novel function for sADAM33.
Furthermore, in genetically susceptible A/J mice, I have found that maternal allergy suppresses
ADAM33 expression in the offspring and that this is associated with reduced airways smooth muscle
and increased airway reactivity. This suggests a gene-environment interaction that leads to altered
airway structure and function. Based on these observations I now wish to test the hypothesis that
ADAM33 influences bronchial smooth muscle growth to affect airway development and that
environmental factors in utero interact with ADAM33 leading to a vulnerable airway structure that
predisposes to the development of asthma in childhood or later in life.
Objectives & Methods:
To test my hypothesis I will address these questions:
1. What is the effect of maternal allergy on airway development and its consequences on airway
structure and function in juvenile mice? This will involve in depth imaging of the airway structure
and correlation with airway mechanics and function. To assess the potential for gene-environment
interactions, the studies will use both A/J (BHR1/ADAM33 positive) and BALB/c (BHR1 negative)
2. Does release of sADAM33 affect smooth muscle growth, airway development and post natal
airway function? This will be assessed using a conditional transgenic mouse expressing sADAM33;
the consequences of altered structure on airway function will be assessed.
3. Do the ADAM33 mechanisms identified in murine lung development occur in developing human
lungs? This will be assessed using gain or loss of function approaches applied to human embryonic
lung explants. I will determine whether sADAM33 is detectable in vivo in amniotic fluid from allergic
mothers and BALF from paediatric asthma patients.
Scientific opportunities: These studies will provide new insight into gene-environment
interactions in utero and their effect on the early origins of asthma. This might lead to novel
prevention and intervention strategies early in life.


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