Factors That Determine The Optimal Concentrations Of Par2 Essay

Factors That Determine The Optimal Concentrations Of Par2 Essay

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c.2b Dose response studies for PAR2 activity modulators in vivo. Initially we will determine the optimal concentrations of PAR2 modulating compounds to use for the studies and assess for toxic effects in our humanized PAR2 mouse. After administering PAR2 modulating compounds to the lungs we will estimate their half-life in both lung and serum using HPLC/MS. While detailed pharmacokinetics of the PAR2 modulating compounds is not a central goal of this application, this will assist optimizing dosing of the PAR2 modulating compounds. After pharmacokinetic assessment we will determine optimal concentrations of the compounds for in vivo studies. A limited number of PAR2 humanized mice (three mice/concentration of PAR2 modulator x eight concentrations) will be used to determine optimal doses. Initial concentration ranges will be determined by the in vitro testing already completed or done as part of Specific Aim 1. We will assess a one week exposure to of PAR2 modulating compounds, the same as shown in our preliminary data. It is possible, if not likely, that there could be more than one dose of these compounds that has a biological effect. Table 1 shows the effect of these compounds in vitro, and demonstrates that some of them have partial agonism or antagonism depending on their concentration. We will select the optimal concentrations that impact inflammation, sensitization, or lung function and analyze them in greater detail and with better resolution in c.2c.
Planned observations to assess responses to PAR2 modulating compounds include lung inflammation (BALF for total cells, neutrophils, eosinophils, and macrophages as well as semi-quantitative histologic assessment). We will use ELISA (on BALF) and RTPCR (on lung tissue) to as...


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...out we have in hand, and we have received institutional funding for this and have ordered the mice. If there were insurmountable problems the experiments could be completed with non-humanized wild-type C57B6 mice. Both the PAR2-/- and the humanized PAR2 mouse are on C57B6 backgrounds.
The research environment provides all the institutional support needed to successfully complete and analyze the proposed experiments. The proposed analysis of the mice involves techniques that our laboratory has developed expertise in, including allergen exposure in mice, assessment of lung function by Flexivent, and the immunologic assessment of allergic lung inflammation. Alternatives, such as using multiplexed bead arrays for cytokine analysis and using morphometric analysis of lung tissue if semi-quantitative histology scoring lacks resolution for the studies will be considered.

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