Asthma is considered the most common chronic disease of childhood, and over 9 million children in the United States have asthma. Mold exposure is significantly associated with the development of asthma. Recently, there has been significant interest in the anti-inflammatory role of Foxp3+ regulatory T (Treg) cells in asthma. In murine models of allergic airway disease, depletion of Treg cells exacerbates inflammation, while adoptive transfer of Treg cells can prevent allergic inflammation, highlighting the crucial role of Treg in modulating the asthma phenotype. Preliminary data from our lab indicates that after mold exposure the ratio of CD25+Foxp3+ Treg cells to CD25+Foxp3- activated T cells is decreased. Further, the literature suggests that one mechanism controlling Foxp3 expression is DNA methylation of the Foxp3 locus. Our central hypothesis is that mold exposure increases the proportion of CD4+ T cells with a methylated TSDR and that inhibition of methylation will increase Foxp3 expression thereby attenuating the asthma phenotype. We will test this hypothesis and accomplish the objectives of this application with the following specific aims.
Aim 1 : Determine the methylation status of the TSDR in CD4+ T cells isolated from mold-challenged mice.
This aim will test the working hypothesis that CD4+T cells from mice challenged with the mold C. cladosporioides will have increased methylation at the TSDR. To address this hypothesis, we plan to challenge mice with C. cladosporioides and assess TSDR methylation using methylation specific sequencing.
Aim 2 : Evaluate the impact of DNA methyltransferase (DNMT) inhibition on Foxp3 expression in mold-induced allergic airway disease.
This aim will test the working hypothesis that treatment with a DNMT inhibitor will result in decreased methylation of the TSDR and consequently increased expression of Foxp3. To address this hypothesis, we plan to challenge mice with C. cladosporioides along with a DNMT inhibitor and assess methylation at the TSDR, Foxp3 expression, levels of activated and regulatory T cells. In addition we will characterize the presence and severity of allergic airway disease by assessing lung function, inflammation, and goblet cell hyperplasia in mice treated with a DNMT inhibitor. Identification of a possible mechanism controlling Foxp3 expression in asthma will have a significant impact on our understanding of how to control allergic inflammation. Further, it may lead to the development of therapies specifically targeting Foxp3+ Treg cells.
This application will investigate anti-inflammatory mechanisms in asthma, in particular the regulation of the molecule Foxp3. Understanding how to modulate anti-inflammatory mechanisms in asthma is critical for the development of more specific therapies to treat asthma.
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