This application is for a K08 Mentored Clinical-Scientist Development Award investigating the novel role of platelet-derived serotonin (5-HT) in mediating pulmonary vascular remodeling and inflammation in neonatal pulmonary hypertension (PH). The candidate is a neonatologist at the University of Colorado who has been studying 5-HT biology in the context of neonatal PH for the past seven years. Pulmonary hypertension (PH) is a life-threatening condition that affects infants, children and adults. There are major deficiencies in our understanding of the pathogenesis of PH, particularly in the developing lung, leading to limited treatment strategies, significant morbidities and mortality rates of 26-43%. The pathophysiology of neonatal PH is complex and multifactorial, and involves alterations in several signaling pathways, including 5-HT. The majority of 5-HT is found within circulating platelets. Platelets and platelet-derived 5-HT have been recognized as key mediators of vascular inflammation in other disease settings. There is now consensus that vascular inflammation is a central component to the pathogenesis of PH in several animal models and humans with PH. Her group has established that PA fibroblasts are critical for vascular remodeling and inflammation in PH. This proposal will test the hypothesis that platelet-derived 5-HT promotes fibroblast activation (proliferation and synthesis of inflammatory mediators) and vascular remodeling in PH.
Aim 1 is to establish the mechanism leading to increased plasma 5-HT in PH.
Aim 2 is to determine if platelet-derived 5-HT promotes proliferation and inflammatory activation of pulmonary fibroblasts.
Aim 3, uses mice genetically depleted of platelet 5-HT and pharmacologic inhibition of 5-HT signaling to determine if platelet-derived 5-HT contributes to pulmonary vascular remodeling, inflammation, and PH in vivo. She uses complementary in vivo methods and in vitro systems to interrogate these aims. Dr. Delaney's early work focused on the role of 5-HT in modulating fetal pulmonary vascular tone using an ovine fetal model of PH. This work provided her with a strong foundation in physiology, pharmacology, and large animal model systems. She has since recognized a critical need to explore the mechanisms by which 5-HT contributes to pulmonary vascular remodeling in PH as vascular remodeling is a principal feature of medically refractory PH, with poorly understood pathobiology leading to high mortality. While the fetal sheep model offers several advantages, Dr. Delaney made the active decision to transition her research to a mouse model of PH in order to (1) elucidate the source of increased 5-HT in PH and (2) use gene targeted mice to explore mechanistically how 5-HT leads to vascular remodeling and inflammation in PH. She has established a mentorship team of premier scientists in the fields of PH and platelet biology, and local advisors in complementary areas of investigation to support her and assure her path towards independence during this award period. This K08 award will allow Dr. Delaney four years of protected research, and aid her scientific development by allowing her to (1) gain expertise in performing and interpreting platelet assays, flow cytometry, molecular techniques, and rodent echocardiography and (2) develop expertise in developmentally regulated 5-HT signaling and platelet mediated inflammation. This additional training in experimental techniques, developmental biology and cell signaling is essential and will prepare her to submit a R01 by the end of her K08 award period. Dr. Delaney's long term academic and research goal is to develop into an accomplished and independent physician-scientist with an expertise in 5-HT mediated PH who can identify and answer fundamental knowledge gaps in developmental biology that contribute to adverse cardiopulmonary conditions in newborn infants. She has demonstrated her commitment to this long-term goal and is in an outstanding academic environment to attain this goal. She has the experience, strong research background, mentorship, institutional support, and focus to excel. She is fortunate to have identified committed mentors with individual areas of expertise that complement but are different from her research focus; thus assuring the development of her scientific independence. Ultimately as a physician-scientist, Dr. Delaney is committed to solving problems in lung development and injury that continue to plague preterm and term infants.
Pediatric pulmonary hypertension most commonly occurs in infants with structural and functional lung disease, resulting in significant morbidity and mortality. This project will determine the mechanisms for platelet-derived serotonin mediated pulmonary vascular remodeling and inflammation in neonatal experimental pulmonary hypertension. These results will allow for the development of targeted strategies to decrease inflammation and target serotonin signaling in infants with this devastating condition.
| Sherlock, Laurie G; Trumpie, Ashley; Hernandez-Lagunas, Laura et al. (2018) Redistribution of Extracellular Superoxide Dismutase Causes Neonatal Pulmonary Vascular Remodeling and PH but Protects Against Experimental Bronchopulmonary Dysplasia. Antioxidants (Basel) 7: |
| Delaney, Cassidy; Sherlock, Laurie; Fisher, Susan et al. (2018) Serotonin 2A receptor inhibition protects against the development of pulmonary hypertension and pulmonary vascular remodeling in neonatal mice. Am J Physiol Lung Cell Mol Physiol 314:L871-L881 |
