Prenatal Programming of Neonatal Asthma Susceptibility Abstract/Project Description Problem and Hypothesis: Asthma begins in early life, and is linked to immune dysfunction that skews responses towards allergy. Human epidemiology identifies 'prenatal programming'for asthma susceptibility through the risk factor of maternal asthma. Our pilot data in maternal allergy reveal that the neonatal dendritic cell (DC) is the critical cellular agent of asthma susceptibility, since adoptive transfer of DCs from asthma- susceptible juvenile mice causes new asthma risk in otherwise normal pups. Genome-wide analysis of DNA methylation shows substantial differences in 'asthma-susceptible'DCs compared to controls. In addition to maternal asthma, other environmental exposures (e.g. tobacco smoke, air pollution) cause neonatal asthma risk, but mechanisms remain poorly characterized. Our experimental studies in normal mother mice show that various 'environmental stressors'all result in babies that are more susceptible to developing allergic airway disease. Our central hypothesis is that multiple environmental stressors cause early life asthma susceptibility through epigenetic modifications in neonatal DCs, which confer pro-asthmatic skewing of immune responses.
Specific Aims :
Aim 1 will use adoptive transfer of DCs to test the postulate that multiple maternal exposures (air pollution, chemical dermatitis, stress) all produce an altered 'asthma-susceptible'DC, similar to that observed in offspring of mothers with OVA-induced allergic asthma. DC subpopulations will be further characterized to optimize epigenetic analyses.
Aim 2 will use genome-wide and targeted epigenetic analysis to test the prediction that 'asthma-susceptible'DCs will share epigenetic marks linked to skewing towards a pro- asthmatic DC phenotype.
Aim 3 will test the hypothesis that the shared mechanism for myriad maternal 'environmental stressors'is a transplacental stress hormone response which causes the epigenetic and functional changes seen in 'asthma-susceptible'neonatal DCs Impact &Significance: The planned studies will identify how multiple environmental exposures of pregnant mothers cause asthma risk, and will provide targets for public health and therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES017588-05
Application #
8450883
Study Section
Special Emphasis Panel (ZRG1-RES-B (03))
Program Officer
Nadadur, Srikanth
Project Start
2009-07-14
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$345,720
Indirect Cost
$129,607
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Turcotte-Tremblay, Anne-Marie; Lim, Robert; Laplante, David P et al. (2014) Prenatal maternal stress predicts childhood asthma in girls: project ice storm. Biomed Res Int 2014:201717
Lim, Robert; Fedulov, Alexey V; Kobzik, Lester (2014) Maternal stress during pregnancy increases neonatal allergy susceptibility: role of glucocorticoids. Am J Physiol Lung Cell Mol Physiol 307:L141-8
Lamoureux, Denise P; Kobzik, Lester; Fedulov, Alexey V (2010) Customized PCR-array analysis informed by gene-chip microarray and biological hypothesis reveals pathways involved in lung inflammatory response to titanium dioxide in pregnancy. J Toxicol Environ Health A 73:596-606
Lim, Robert H; Kobzik, Lester; Dahl, Morten (2010) Risk for asthma in offspring of asthmatic mothers versus fathers: a meta-analysis. PLoS One 5:e10134