This proposal describes a 5-year training program that will further develop the primary investigator as a full-fledged clinical scientist, combining his expertise in pediatric pulmonary medicine, with new skills and experience critical for success as independent investigator. Using both hypothesis-driven and hypothesis - generating approaches, this proposal will investigate mechanisms underlying asthma risk in early life. Multiple maternal exposures increase asthma risk in offspring, but the mechanisms remain uncharacterized. My central hypothesis is that maternal stress responses constitute a shared mechanistic pathway by which these various exposures induce increased asthma susceptibility in offspring. The specific postulate to be tested is that this susceptibility is mediated via a stress hormone (corticosterone) dependent pathway that alters neonatal/fetal CD4cell function through epigenetic (DNA methylation) modifications.
In specific aim 1, a mouse model for stress-induced maternal transmission of asthma risk will be further characterized and the role of stress hormones determined.
In specific aim 2, the role of neonatal CD4 cells will be determined by testing for a Th2-skewed cytokine profile and by adoptive transfer of naive CD4cells from asthma-susceptible neonates to normal pups. In the specific aim 3, epigenetic differences in DNA methylation of these cells in normal, asthmatic, and asthma-susceptible mice will be determined using site-specific and global discovery approaches. The most promising subset of epigenetic marks will be tested as biomarkers of asthma risk in human neonatal T cells. In addition to a rigorous experimental plan, the project includes structured training in immunology, epigenetics, and bioinformatics using coursework, seminars and guidance from an expert advisory committee. The experienced sponsor details a mentorship plan for development of career skills and scientific independence. The combination of a focused research project and rigorous training plan will allow the applicant to achieve a success as an independent clinical scientist, as envisioned by the K08 award.
Asthma is a major public health issue. Maternal asthma confers greater risk of asthma to offspring then does paternal, and other maternal exposures also increase susceptibility. This study will elucidate the underlying mechanisms for neonatal asthma risk and will add to the understanding of asthma pathogenesis. It will also identify human blood biomarkers for asthma susceptibility, which may improve prevention and therapy.
