This proposal describes a 5-year training program to provide Dr. Deepthi Alapati, MD, MS, Attending Neonatologist at Nemours AI duPont Hospital for Children with the mentorship, training and research experience required to become an independent clinician scientist and a leader in neonatal lung disease research. She has received a Master?s degree in Translational Research from University of Pennsylvania. Candidate?s long-term career goal is to develop novel therapies to promote lung repair and regeneration for treatment of neonatal lung diseases such as bronchopulmonary dysplasia (BPD). To achieve these goals, she will be mentored by a team of internationally recognized experts in pulmonary basic science research from Nemours and University of Pennsylvania with whom she has a proven track record of successful mentorship and productivity. She will undergo a rigorous didactics and hands-on training program to acquire expertise in elucidating pulmonary cell-specific molecular mechanisms within the lung microenvironment using complex genetic mouse models and 3D co-culture systems; application of gene editing technologies as a mechanistic and therapeutic tool to modulate candidate genes in complex lung diseases such as BPD; and expertise in advanced bioinformatics. Her research will focus on (1) elucidating the function of Cellular communication network factor 2 (Ccn2) in alveolar epithelial cells (AEC) during alveologenesis and (2) evaluating whether modulating Ccn2 expression in AEC will improve a hyperoxia-induced BPD phenotype. This research proposal is built upon candidate?s preliminary research that demonstrates an important causative role for Ccn2 in severe BPD and the therapeutic potential of CRISPR-Cas9 gene editing technology to manipulate disease causing genes expressed in the developing pulmonary epithelium. BPD is the most common cause of death, severe neurodevelopmental impairment, and hospital readmissions in preterm infants. In spite of advances in clinical care, clinical efforts to prevent and treat BPD have been largely unsuccessful. As the cell type most exposed to the external environment, AEC have emerged as a central focus in many lung diseases, including BPD. Moreover, AEC can be directly targeted by therapeutic agents delivered through intra-amniotic, intra-nasal and intra-tracheal routes. Thus, a better understanding of mechanisms in AEC that drive alveologenesis during normal lung development and in response to early postnatal lung injury, would pave path for targeted therapies for severe BPD. By precisely examining the spatial and temporal function of Ccn2 in AEC during alveologenesis and early postnatal lung injury induced by hyperoxia, this study will provide novel mechanistic insights into its role in regulating alveologenesis and lead to novel therapies targeted at AEC-derived Ccn2 for the prevention and treatment of severe BPD. Candidate has access to all required technical, laboratory and intellectual resources in an ideal collaborative environment for successfully conducting her research and pave the path to develop as an independent investigator.
Bronchopulmonary dysplasia (BPD) is a serious chronic lung disease of premature babies that causes life-long cardiorespiratory morbidities and there are no effective treatments available to prevent or treat this disease. Infants who died because of BPD have increased levels of Cellular communication network factor 2 (CCN2) in their lungs. This study will use animal models to evaluate the function of CCN2 in lung cells during normal lung development and during disease, and evaluate whether decreasing the production of CCN2 in lung cells will prevent BPD.
