?Bronchopulmonary dysplasia (BPD) is characterized by abnormal lung development before or soon after birth. The condition can cause serious complications during infancy and often requires intensive medical care. The risk of developing BPD increases the earlier a baby is born and the lower the birth weight. Many infants diagnosed with BPD today are born at far earlier gestational ages than in the past because advances in perinatal care have enabled doctors to keep more extremely premature babies alive than in the past. The National Institutes of Health estimates that >12,000 babies born in the United States develop BPD each year. Impairment of the lungs in BPD patients represents an underlying disruption or abnormality in the development of the lungs. Current management of BPD is geared toward minimizing damage to the lungs and providing enough support to allow an affected infant's lungs heal and grow. Infants with BPD may receive supportive measures that aim to help the baby breathe enough oxygen, stay warm, and have enough fluids and nourishment as well as medications, including corticosteroids, bronchodilators, diuretics and antibiotics. Despite these advances in care, most babies with BPD spend an estimated 120 days in the NICU, and are susceptible to a variety of pulmonary disorders during their life. Clearly, novel therapeutics that can effectively improve alveolarization and pulmonary vascular development in BPD patients is much needed. Recent evidences have suggested a strong link between angiogenesis and alveolarization, and that vascular-specific angiogenic factors could play key roles during normal alveolar development. Importantly, recent advances have shown that the signaling of a group of vascular receptors, CLR/RAMP receptors, is essential for normal vascular development and alveolarization during early development. The activation of CLR/RAMP signaling has been shown to improve alveolarization and vasculogenesis in BPD animal models, whereas the blockage of CLR/RAMP signaling decreases lung capillary density and impairs alveolar development. Based on this understanding, we propose to develop a novel hormonal therapy that target CLR/RAMP receptors to improve alveolarization, blood flow, and vascularization of the underdeveloped lungs in preterm babies. Specifically, we will investigate the pharmacokinetics and efficacy of the novel therapeutic candidates in a rat BPD model. Successful development of this novel therapeutics has the potential to significantly reduce the mortality and morbidity among very preterm babies.
Public Health Relevance Statement: Public Health Relevance: Based on human hormones that are essential for normal vessel development in the cardiovascular and the pulmonary systems, we have developed novel therapeutic candidates for the treatment of bronchopulmonary dysplasia. We will investigate the pharmacokinetics and efficacy of this first-in-class therapeutics in an established bronchopulmonary dysplasia model. Successful development of this therapeutics could significantly prevent or reduce the debilitating effect of bronchopulmonary dysplasia in very preterm babies.
NIH Spending Category: Infant Mortality/ (LBW); Lung; Pediatric; Perinatal - Birth - Preterm (LBW); Perinatal - Neonatal Respiratory Distress Syndrome; Perinatal Period - Conditions Originating in Perinatal Period
Project Terms: Adrenal Cortex Hormones; adrenomedullin; Adult; aerosolized; Affect; Alveolar; Alveolus; analog; angiogenesis; Angiogenic Factor; Animal Model; Antibiotics; Bacterial Infections; base; Birth; Blindness; Blood; Blood capillaries; Blood flow; Blood Vessels; Breathing; Bronchiolitis; Bronchodilator Agents; Bronchopulmonary Dysplasia; capillary; Cardiovascular system; Caring; Cerebral Palsy; Cicatrix; combat; density; design; Development; Diagnosis; Disease; Diuretics; drug candidate; Drug Kinetics; Edema; effective therapy; Embryonic Development; Environmental air flow; Exhibits; Extravasation; Fibrosis; fighting; Gestational Age; Gold; Growth; Healed; healing; Hearing; Heart; Heart Hypertrophy; hormone therapy; Hormones; Hospital Mortality; Hospitals; Human; human NOS3 protein; Hyperoxia; Impairment; improved; in vivo; infancy; Infant; Injury; Investigation; Lead; Length; Length of Stay; Life; Link; Liquid substance; Low Birth Weight Infant; Lung; lung development; Lung diseases; lung injury; Lymphatic; Maintenance; Measures; Medical; Modeling; Molecular; Morbidity - disease rate; Mortality Vital Statistics; Neonatal; Neonatal Intensive Care Units; nervous system disorder; novel; novel therapeutics; Organ; Oxygen; Patients; Perinatal Care; Permeability; Pharmaceutical Preparations; Phase; Play; Pregnancy; premature; Premature Infant; prevent; public health relevance; Pulmonary Hypertension; RAMP1; Rattus; receptor; Receptor Signaling; Respiratory Tract Infections; Right Ventricular Hypertrophy; Risk; Signal Transduction; Small Business Innovation Research Grant; Staging; surfactant; System; Therapeutic; therapeutic development; Time; Tissues; Toxicology; United States; United States National Institutes of Health; Vascularization; vasculogenesis
