Bronchopulmonary dysplasia (BPD) remains a significant cause for morbidity and mortality in premature neonates. BPD occurs in approximately 1/3 of infants less than 1000 grams and is associated with worse developmental outcomes, increased re-hospitalization and long term complications of lung function. The neonatology community remains without an effective therapy to prevent or treat BPD. There remains a critical need to determine the key regulatory pathways in order to develop novel therapeutic options in the prevention and treatment of BPD. Adenosine is a signaling molecule that regulates pulmonary processes including inflammation and alveolar development, and there is significant evidence that adenosine could be a critical regulatory pathway in BPD. However, its role in the pathophysiology of BPD remains unknown. The overall hypothesis is that adenosine signaling in premature neonates disrupts normal alveolar repair and contributes to the inflammation and disrupted alveolar development observed in BPD.
Aim 1 will utilize an animal model of BPD to determine adenosine's regulation of repair including pulmonary inflammation and alveolar development.
Aim 2 focuses on adenosine's signaling effect on alveolar type 2 cell populations which play an important role in long term consequences of hyperoxia after birth. This project will provide important insight into the role of adenosine signaling in the premature lung and will help-guide the pre-clinical rationale for the long-term goal of developing novel therapeutic strategies targeting adenosine signaling for the prevention and treatment of BPD. Dr. Jonathan Davies has a prolific history of scientific research throughout his training. These projects ranged from basic research, innovative and collaborative research projects, and clinically applicable research projects. Dr. Davies' advancement through his research and clinical training have provided him the ability to assemble a research environment that facilitates success. This includes the physical environment and an outstanding mentorship environment with established and productive researchers with extensive histories of mentoring young scientists to independence. The research and career development plans describe in this proposal are a natural progression for Dr. Davies into a career of independent research with the primary goal of significantly improving the outcomes of premature neonates by developing novel therapies to prevent and treat BPD. Additionally, the career developmental plan included with this award will provide the coursework, conferences and meetings that will complement his clinical work and mentoring by a team of interdisciplinary scientists with relevant expertise. Dr. Davies' training environment is outstanding and includes institutional support with dedicated space and protected time, and scientific support by mentors and collaborators with expertise relevant to his research plans and career goals. This environment will assure success with the proposed project and his advancement in his career towards independent research.
Title: Adenosine Signaling In Bronchopulmonary Dysplasia Bronchopulmonarydysplasia(BPD)remainsasignificantcauseformorbidityandmortalityinpremature neonates.Thereremainsacriticalneedtodeterminethekeyregulatorypathwaysinordertodevelop noveltherapeuticoptionsinthepreventionandtreatmentofBPD.Myproposedworkaimstoevaluate theroleofadenosinesignalingintherepairprocessesinthepathophysiologyofBPDincludingeffectson pulmonaryinflammationandalveolardevelopmentintheprematureneonatallung.
