This proposal describes a 5-year training program for the development of an independent physician- scientist. The applicant is a junior faculty in Pediatrics and her mentor is Dr. Joshua Hare, Professor of Medicine, and Director of the Interdisciplinary Stem Cell Institute at the University Of Miami Miller School Of Medicine. A leader in the field of stem cell regenerative therapies for cardiovascular disease. Dr. Hare has trained many junior faculty scientists, postdoctoral fellows and graduate students. The curriculum described in this proposal will provide the applicant with the opportunity to acquire a stronger scientific background in stem cell biology as well as neonatal cardiopulmonary physiology. The applicant's research will focus on understanding the role of c-kit in the development of neonatal hypoxia-induced pulmonary hypertension (PH). PH affects approximately 1 in 1000 neonates per year and remains one of the leading causes of mortality in this population, c-kit is a tyrosine kinase receptor which is mainly studied as a stem cell marker;however its role in PH is unknown. Our preliminary data have demonstrated increased c-kit cells in the pulmonary arteries and right ventricles (RV) of neonatal mice with PH. We hypothesize that c-kit cells participate in hypoxia-induced pulmonary vascular remodeling by a) differentiating into myofibroblasts or b) directing the secretion of angiogenic, mitogenic and survival factors which exacerbate pulmonary vascular remodeling.
The specific aims are: 1) To characterize the phenotype and temporal-spatial distribution of native and BM-derived c-kit cells in the pulmonary vasculature of neonatal mice with chronic hypoxia- induced PH. 2) To elucidate the mechanisms which regulate the homing and activation of c-kit cells during neonatal chronic hypoxia-induced PH. 3) To determine whether c-kit progenitor cells participate in PH by differentiating into mature pulmonary vascular cells or by secreting mitogenic, angiogenic and survival factors. The University Of Miami School Of Medicine is the ideal environment for this training program as it has the unique combination of state of the art resources and leading scientists of diverse backgrounds. The proposed research training plan will include participation in didactic courses, as well as regular reviewing of the candidate's progress by an expert advisory committee. It is expected that this award will allow the candidate to become an independent investigator with expertise in cardiopulmonary and stem cell biology.
Recently, there has been a flurry of new therapeutic modalities which have vasodilated the pulmonary vasculature, but few have significantly decreased the vascular remodeling that is evident during PH. These studies will expand our fundamental knowledge of the role of stem cells in neonatal pulmonary vascular remodeling and provide a solid foundation for the development of novel therapeutic strategies.
|Young, Karen C; Torres, Eneida; Hehre, Dorothy et al. (2016) Antagonism of stem cell factor/c-kit signaling attenuates neonatal chronic hypoxia-induced pulmonary vascular remodeling. Pediatr Res 79:637-46|
|Ramachandran, Shalini; Suguihara, Cleide; Drummond, Shelley et al. (2015) Bone marrow-derived c-kit+ cells attenuate neonatal hyperoxia-induced lung injury. Cell Transplant 24:85-95|
|Drummond, Shelley; Ramachandran, Shalini; Torres, Eneida et al. (2015) CXCR4 blockade attenuates hyperoxia-induced lung injury in neonatal rats. Neonatology 107:304-11|
|Miranda, Luis F; Rodrigues, Claudia O; Ramachandran, Shalini et al. (2013) Stem cell factor improves lung recovery in rats following neonatal hyperoxia-induced lung injury. Pediatr Res 74:682-8|