The Effect Of Modulation Of Par2 Signaling Using Vivo Vitro Models Of Allergic Asthma

The Effect Of Modulation Of Par2 Signaling Using Vivo Vitro Models Of Allergic Asthma

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(120-126). However, we have recently shown that our potent/specific PAR2 activators can act apically to alter salt and water movement in primary cultured mouse tracheal epithelial cells (109), and thus have developed a model that better fits natural exposure in healthy and/or susceptible individuals -- apical application. Because PAR2 expression has been reported to increase in asthmatic airways (74), and, because increased PAR2 expression in animal models increases the inflammatory response (106), if time allows, we will consider using asthmatic cell cultures (available from Lonza) in our experiments to better evaluate the ability for optimized PAR2 modulators to affect asthmatic allergic response.
While the compounds in hand (C608, C562) will allow for the first pharmacological examination of PAR2-biased signaling in an asthma model, experiments with PAR2-modulators that preferentially block -arrestin/MAPK PAR2 signaling will be prioritized as they are developed in our independently funded drug-dicovery program.
c.2 Specific Aim 2: Determine the impact of modulation of PAR2 signaling using in vivo models of allergic asthma. Our preliminary data show PAR2 signaling activates two signaling pathways with biased activation potentially leading to either inflammation or bronchorelaxation. The focus of these experiments will be to determine how PAR2 modulation (activation, inhibition, or biased activation/inhibition) impacts inflammatory responses and lung resistance based on the disparate roles of these pathways activated by PAR2.
There are several strengths of Specific Aim 2 that will allow us to understand the role of PAR2 in asthma by studying the specific pathways of PAR2 signaling. We have an existing set of PAR2 activity modulat...


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...nce is reduced by cotreatment with the PAR2 inhibitor C391 (Figure 15). Taken together, these show that localized inhibition of PAR activity in the lung during allergen exposure is sufficient to mitigate inflammation, mucus production, and lung resistance, all critical components of asthma. We demonstrate the feasibility to perform these studies with other PAR2 modulators including biased agonists and to investigate the role of PAR2 modulation in severe asthma and asthma caused by allergens that are not associated with protease activity. These preliminary data show that the outcomes planned are relevant both to PAR2 modulation and to lung physiology and immunology. They also show that our laboratory has the expertise to perform these experiments with the precision to interpret subtle differences in lung immunology and physiology caused by PAR2 modulating compounds.

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