The overall objective of this NRSA Individual Fellowship is to develop skills that will allow the candidate to become a physician-scientist and pursue an academic research career. The applicant and his mentors have devised a training approach that includes both research and didactic instruction. This approach will establish the knowledge and intellectual framework essential for a successful research career. The proposal concerns acute lung injury (ALI) in neonates and juveniles. Pediatric acute lung injury represents a major global source of morbidity and mortality. Pneumonia-associated ALI in neonates accounts for 10% of annual childhood deaths. Despite the healthcare burden associated with this disease, the mechanisms through which pediatric ALI resolves remain unknown. Regulatory T cells (Tregs), a subset of cells in the adaptive immune system that suppresses exuberant immune responses, have been shown to play a critical role in lung injury resolution in an adult mouse endotoxin (LPS) model of ALI. There is, however, little data on the role and function of Tregs in pediatric ALI. Tregs play an important role in fetal life by suppressing auto-reactive immune cells and preventing inflammation that may lead to fetal loss;however, these cells may be functionally impaired in the newborn as the immune system transitions from a tolerant state to a pro-inflammatory one. The candidate has preliminary data showing in neonates, unlike in juvenile mice, alveolar Treg numbers do not increase following LPS- mediated lung injury. Increasing Treg number by adoptive transfer enhances resolution and restores normal growth and development in LPS-injured neonates. The focus of this proposal is to further examine the factors that contribute to the diminished Treg response in neonates with the long term hope of discovering novel therapeutic targets for children with ALI.
In Specific Aim 1, the candidate will examine the differences in the Treg response of neonatal and juvenile mice following lung injury. Multicolor flow cytometry will be used to determine Treg kinetics and phenotype. Adoptive Transfer of neonatal Tregs into Treg-depleted adults and suppression assays will measure in vivo and ex vivo Treg function.
Specific Aim 2 will define the IL-2/CD25 axis modulation of the neonatal Treg response. The candidate will determine age-dependent IL-2 expression by real time PCR and ELISA. He will also define the ability of exogenous IL-2 administration to expand Treg numbers, increase suppressive function, and enhance acute lung injury resolution. These experiments will explore the mechanisms controlling neonatal Treg function following acute lung injury with the ultimate hope of improving patient outcomes in this lethal disease.
Acute lung Injury (ALI) is a common and mortal condition in children, likely reflecting the immature responses of the developing immune system. In adults, regulatory T cells (Tregs) play a critical role in resolving ALI inflammation;however, in neonates regulatory T cells are less effective at responding to this inflammatory insult. We hope to identif novel mechanisms that account for age-related differences in Treg function and, ultimately, discover new therapeutic options by studying how the IL-2/CD25 axis affects Tregs during pediatric lung injury resolution.