Lung Injury Biomarkers to Endotype Respiratory Trajectories in Established Bronchopulmonary Dysplasia: The LIBERATE-BPD Study

/ABSTRACT: The purpose of this Mentored Patient-Oriented Research Career Development Award (K23) is to provide Dr. Matthew J. Kielt, MD, Assistant Professor of Pediatrics at The Ohio State University College of Medicine and Nationwide Children’s Hospital with the requisite mentorship, training, and research experience to become an independent clinician-scientist with niche expertise in precision medicine clinical trials. His long-term goal is to identify precision therapeutics that restore normal pulmonary function in infants with bronchopulmonary dysplasia (BPD). His immediate goal is to develop the skills needed to lead multi-center biomarker-driven clinical trials of anti-inflammatory therapeutics for infants with BPD. To achieve these goals and transition to independence, Dr. Kielt and his mentorship team have developed a comprehensive career development plan that includes: (1) intensive mentorship from an R01 funded team with a proven record of K-award mentorship; (2) didactic and hands-on training in precision medicine research methods, advanced longitudinal statistical analyses, and the conduct and design of clinical trials; and (3) an innovative research proposal to develop biomarker-informed prognostic models for infants with BPD. Preterm infants with the most severe form of BPD, grade 3, are ventilator-dependent near term corrected age and suffer from chronic pulmonary insufficiency throughout life. Infants with grade 3 BPD exhibit striking heterogeneity in the time required to wean from mechanical ventilation (MV). Infants with grade 3 BPD who are difficult-to-wean from MV, defined as unsuccessful liberation from MV by 2 months’ corrected age, are at 3-fold increased risk of death as compared to infants who are simple-to-wean. Biologic predictors that discriminate grade 3 BPD infants who are and are not difficult-to-wean remain unknown. In adult critical care patients, pathogenesis-informed biomarkers of lung inflammation discriminate patients who are and are not difficult-to- wean. Additionally, biomarker-driven clinical trials in adults demonstrate that budesonide, an inhaled cortico- steroid that reduces pulmonary inflammation, decreases the expression of pro-inflammatory biomarkers, and facilitates weaning from MV. Whether these findings are generalizable to infants with grade 3 BPD constitutes an important knowledge gap. Dr. Kielt's research proposal will address this knowledge gap by (1) determining the discriminatory performance of pro -inflammatory biomarkers for grade 3 BPD infants who are and are not difficult-to-wean from MV and (2) demonstrating the feasibility of a biomarker-driven clinical trial of budesonide in infants with grade 3 BPD. The expected outcomes of Dr. Kielt's K23 studies will yield novel insights into grade 3 BPD disease progression that will inform the design of pioneering R-series biomarker-driven randomized controlled trials of anti-inflammatory therapeutics. His career development plan outlines a clear path to gain the knowledge, skills, and experience needed to become an independent and innovative clinician- scientist who leads multi-center BPD precision medicine clinical trials. Project Number: 1K23HL175207-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Matthew Kielt | Institution: RESEARCH INST NATIONWIDE CHILDREN'S HOSP, COLUMBUS, OH | Award Amount: $179,330 | Activity Code: K23 | Study Section: Special Emphasis Panel[ZHL1 CSR-Z (J2)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K23HL17520701A1