The area of research has been the effects of group B streptococcus (GBS) on diaphragmatic function in the neonatal piglet. This work has been supported by research and fellowship training grants from the American Lung Association (ALA) of Washington, and is now supported by research grants from Children's Hospital of Pittsburgh and the ALA (National). The investigator now seeks to expand the breadth of training in muscle physiology in order to provide a cellular explanation for the observed changes in diaphragmatic function in piglets infused with GBS. The proposed research plan is designed to study the mechanism behind the decrease in diaphragmatic force generation (Pdi) during GBS infusion in piglets. It has now been demonstrated that thromboxane A2 (TXA/2) is the putative mediator for diminished GBS infusion in piglets. Now that an in vivo role for TXA/2 during GBS infusion has been demonstrated, the next step is to demonstrate that TXA/2 exerts an effect on diaphragmatic contractility in vitro, as pilot data strongly suggests it shall. The proposal will explore potentia mechanisms by which TXA/2 might exert an in vitro effect, following leads suggested by preliminary data. The proposal will examine sarcoplasmic reticulum Ca2+ release, membrane action potential and excitation-contraction coupling, Ca2+ sensitivity and the maximal Ca2+-activated force. The research is to be conducted within the research training environment of the Children's Hospital of Pittsburgh and the University of Pittsburgh, in the laboratory of the Pediatric Pulmonology Division, the Department of Pediatrics; and the Department of Cell Biology and Physiology. Drs. Fuchs, Professor and Acting Chairman in the Department of Cell Biology and Physiology, with an expertise in muscle physiology, will supervise the research and facilitate the candidates development into an independent investigator.
