This proposal describes a 5-year physician scientist development plan that will provide the necessary training and skills to progress towards a successful career as an independent investigator. The plan emphasizes integration of scholarly activities, laboratory training, and Advisory Committee mentoring to foster career development. The applicant has recently completed fellowship training in Neonatology at the University of Connecticut Health Center. During this time the principal investigator became involved in research focusing on the immunologic interaction between the mother and offspring. This career development award will provide the necessary "time" and structured "support" to build an independent research career in the field of maternal, fetal, and neonatal immunology. Dr. Lynn Puddington is an accomplished investigator in the field of neonatal immunology and will serve as the candidate's Sponsor. Dr. Roger Thrall, an authority on various aspects of lung biology and pulmonary inflammation, will serve as Co-sponsor. Together with an outstanding group of Advisory Committee members and scientific collaborators this group will provide valuable insight and support towards becoming a physician scientist. Research will focus on characterizing the ability of specific components in breast milk to alter allergic risk in offspring. We have identified two factors (antibody and antigen) transmitted from mother to neonate during breastfeeding that result in the attenuation of allergic airway disease in offspring. In this application we will adapt our models of maternal influence to define how these maternal factors mediate their protective effects in offspring. To this end we propose to: 1) Characterize the interaction of maternal immunoglobulins and FcRn in maternal transmission of allergic resistance;and 2) Characterize how antigen inhalation during lactation contributes to altered immune responsiveness in offspring. The results generated from these studies will be relevant because they will identify transmissible maternal factors capable to reduce the adverse consequences of allergic sensitization in early life. Furthermore, this will be the first detailed analysis of how maternal antigen inhalation during lactation contributes to attenuated allergic disease in offspring. Despite advances in our understanding of its pathogenesis and therapy, allergic diseases such as asthma have become an increasingly prevalent health problem world wide. Even with moderate asthma, it is difficult for children to focus on their work while under the influence of the anti-inflammatory medications used for treatment. It is only after the controlling factors that influence allergic disease are elucidated that therapeutic strategies can be rationally designed to interrupt this process in childhood.
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