Prenatal Programming of Neonatal Asthma Susceptibility

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DESCRIPTION (provided by applicant): Human epidemiology identifies 'prenatal programming' for asthma susceptibility through risk factors such as maternal asthma or environmental exposures (e.g. second-hand smoke), but mechanisms remain unclear. Our experimental studies in mice show that various 'environmental stressors' (e.g., allergens in 'asthmatic' mother mice, air pollution particles, stress) all result in a mother whose babies are more susceptible to developing allergic airway disease. This asthma susceptibility is mediated by the neonatal dendritic cell (DC), in association with distinct epigenetic changes (DNA methylation). Our R01 project is pursuing the mechanisms and epigenetics of prenatal programming of asthma susceptibility in mice. Our ViCTER program will extend these investigations into human biology. The central hypothesis is that epigenetic modifications in human neonatal DCs and lung epithelial cells are linked to asthma susceptibility. Our ViCTER research will translate the animal model data into human studies through three specific aims. Specific Aims: Aim 1 will extend the lead applicant's epigenomic analysis of prenatal programming of asthma risk to relevant human samples, in close collaboration with the consortium members. This aim will use genome-wide methylation arrays to analyze epigenetic changes in samples obtained in aims 2 and 3. Aim 2 will specifically compare the DNA methylome of 'asthma-susceptible' versus normal human neonatal dendritic cells. We will perform targeted and genome-wide analysis of DNA methylation marks in human neonatal cord blood DCs, obtained from the consortium members in Nara (Japan), from well-characterized asthmatic, smoking or normal mothers. Aim 3 will compare DNA methylation profiles in key genes of another cell type critical in asthma, the lung airway epithelial cell, isolated from 'asthma-susceptible' versus normal human fetal lungs. The consortium members (Boston, MA) will use normal fetal lung tissue, archived after elective abortion, from mothers who are normal (controls), smokers (second-hand smoke effects on fetus), or asthmatic. After laser-capture microdissection (LCM) to isolate airway epithelium, comparison of the stable DNA methylation marks will evaluate targeted epigenetic changes linked to asthma susceptibility. These ViCTER studies will extend our R01 project into human pathobiology, test the central hypothesis and develop the foundation for future studies of prenatal epigenetic programming by environmental exposures. The combined mouse and human studies will help identify how multiple environmental exposures of pregnant mothers cause asthma risk, and will provide targets for public health and therapeutic interventions.