""""""""Ambient Pollutant/Bioaerosol Effects on Treg Function"""""""": The basic biological mechanisms by which ambient air pollution affects the human body have been studied mainly in the areas of oxidative stress, DNA damage, and airway epithelial changes [Galli, 2008 #345]. Some studies have focused on the downstream, unregulated inflammatory responses that result from Th2 polarization associated with ambient air pollution exposure[Bernstein, 2004 #194;Devouassoux, 2002 #55;Diaz-Sanchez, 1999 #60;Diaz-Sanchez, 2000 #58;Diaz-Sanchez, 2000 #57;Diaz-Sanchez, 2005 #188;Diaz-Sanchez, 1996#67;Diaz-Sanchez, 1997 #64;Finkelman, 2004 #53;Fujieda, 1998 #70;Riedl, 2005 #52;Sawant, 2008 #49;Saxon, 2005 #107]. However, I propose to study the effects of ambient air exposure on Treg, and test the hypothesis that specific decreases in Treg function consequent to this exposure are a major component of the immunopathology of asthma. In fact, the lack of normal Treg function in the lung is associated with asthma in children [HartI, 2007 #277]. Treg represent the basic counterregulatory arm of the immune system in human development;however, little is known on how ambient air pollution affects Treg differentiation and function. My laboratory has performed studies on Treg isolated from blood samples of children living in the Central Valley in collaboration with the Fresno Asthma Children's Environmental Study (FACES) [Margolis, 2008 #435;Tager, 2006 #72;Tager, 2005 #240;Tager, 1998 #242] in which chronic exposure to ambient air pollution has been measured. I have found that Treg function is attenuated by up to 10 fold compared to controls;in addition, this impairment is associated with direct decreases in Foxp3, a gene associated with Treg development and function in humans [Hori, 2003 #280;Ono, 2007 #1111;Sakaguchi, 2003 #279]. Combined with rigorous epidemiological studies, the innovative functional and molecular tools proposed in project 3 would allow for observations about environmental exposure in children to become more fundamental at the basic science level. Specifically, 1 propose:
Specific Aim 1 to define the mechanisms of Treg impairment in non asthmatic and asthmatic children and Specific Aim 2: to evaluate if Treg dysfunction correlates with estimate individual exposure. The study will generate a unique body of scientific knowledge of detailed exposure and individual follow-up data linked to immune system changes that are otherwise not currently available to advance the field of environmental effects on health. Our approach will address the biologic plausibility of the association between the increase in asthma and ambient air pollution exposure.
Asthma is the leading serious chronic illness among children in the U.S., with an estimated 6.8 million children under age 18 currently having asthma. Our proposed research findings could provide mechanistic explanations for the known association between air pollution exposure and asthma. The results of the proposed study could help shape long-term strategies in the effort to intervene early in the lives of children to decrease and prevent the burden of allergic asthma by reducing their exposure to air pollution.
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