Pediatrics 3

Development

Principal investigators

Prof.Dr N.A. Blom, Dr G. T.M. Wagenaar, Prof.Dr F.J. Walther, Dr AAW Roest

Aim and focus

This program studies development of the lung, heart and skeleton in a basic science setting. Perinatal lung research focuses on the molecular mechanisms of oxidative stress and lung development in chronic lung disease of the newborn using a rat model. Cardiac research includes development of the cardiac conduction system in relationship to clinical arrhythmias, mechanisms of closure of the ductus arteriosus, and advanced imaging (echocardiography, MRI and CT) focusing on cardiac function after congenital heart surgery. Skeletal development studies epiphyseal growth plate regulation and genetic causes of short and tall stature to improve the diagnosis and treatment of childhood growth disorders.  

Position in international context

The various projects are internationally competitive. The LUMC is a leader in the field of cardiac imaging research in congenital heart disease, combining novel echocardiographic and MRI techniques.

Content/highlights/achievements

Perinatal lung research

• Oxidative stress, inflammation and lung immaturity are pivotal contributors to the pathophysiology of chronic lung disease (CLD or bronchopulmonary dysplasia (BPD)) in preterm infants that is characterized by an impairment of cardiopulmonary function by permanent enlargement of alveoli (emphysema) and persistent pulmonary arterial hypertension-induced and right ventricular hypertrophy. The research focuses on the development of novel treatment options for neonatal CLD by reducing inflammation, coagulation and pulmonary arterial hypertension-induced right ventricular hypertrophy, and stimulate alveolarization.
• Stimulation of the endothelial nitric oxide synthase (eNOS)/cGMP pathway with apelin, inhaled nitric oxide or sildenafil and inhibition of phoshodiesterase 4 reduces pulmonary inflammation and restores in part alveolar and vascular lung development, pulmonary hypertension and right ventricular hypertrophy in experimental chronic lung disease.

Cardiovascular research

• Research on the developing cardiac conduction system and formation of the fibrous heart skeleton has led to new insights into the pathogenesis of clinical arrhythmias such as Wolff-Parkinson-White syndrome, and the role of epicardium derived cells on formation of the annulus fibrosis.
• Cardiac dysfunction is frequently observed after correction of congenital heart disease. Using novel echocardiographic and MRI techniques subclinical myocardial dysfunction and abnormalities in electro-mechanical coupling can be observed in patients with “normal” cardiac function as assessed with conventional imaging methods.

Growth plate and growth genetics research

Besides advancing insights into the role of sex hormones on epiphyseal growth plate regulation, skeletal research has been instrumental in unraveling the function of various genetic factors influencing linear growth, including PTHrP, NSD1and APC. Mutations of STAT5B, ALS, IGF-I, IGF1R and NSD1 have been detected in patients with growth disorders.

Future themes

Perinatal lung research

• Reversibility of emphysema by stimulation of angiogenesis-driven alveolar and vascular lung development in neonatal CLD.
• Effect of a second hit (smoking, viral lung infections) on the development of emphysema (premature COPD) following neonatal chronic lung disease.

Cardiovascular research

• Development of the cardiac conduction system in different arrhythmia models.
• Longitudinal imaging of cardiac development using fetal echocardiography in rats.
• Studies on programmed proliferative degeneration of the ductus arteriosus
• Heart failure and cardiac dyssynchrony in patients prior and during follow-up after correction of a congenital heart defect.

Growth plate and growth genetics research

• Continuation of microarray studies on human mesenchymal stem cells differentiating into chondrocytes and on human growth plates
• Expansion of the genetic screen for growth disorders
• Functional studies on a novel gene associated with pituitary development
• Cohesion within LUMC

Lung research is done in close cooperation with the Departments of Pulmonology and Cardiology, cardiovascular research cooperates with the Departments of Anatomy & Embryology, Cardiology and Radiology, and skeletal research is a joint effort with the Departments of Endocrinology & Metabolic Disorders and Human Genetics.