Research

Congenital heart disease is the most common birth defect and is associated with high rates of neurodevelopmental impairments in childhood, adolescence, and adulthood. Brain dysmaturation underlies these impairments and begins prenatally. Our research applies state-of-the-art magnetic resonance imaging (MRI) methods to study brain development in the fetus, infant, and child with congenital heart disease. We are particularly interested in novel MRI approaches that improve mechanistic understanding of the pathways influencing brain development, with the ultimate goal of identifying targeted neuroprotective approaches for improving outcomes. Our current areas of focus for understanding mechanisms of brain dysmaturation include: 

• Prenatal environment and the placenta 
• Cardiac physiology and the intensive care environment 
• Parental wellbeing 
• Social determinants of health 

Our research program is comprised of a multidisciplinary team that spans neonatology, cardiology, psychology, neurology, radiology, and engineering, as well as ongoing collaborations within obstetrics and pediatric pathology. We conduct single- and multi-center projects, all with the aim of understanding brain development and improving neurodevelopmental outcomes for children with congenital heart disease. 

This research focuses on understanding the physiologic basis for brain injury in neonates as well as the development of new methodologies for prediction of neurologic injury. The ultimate goal of these efforts is the development of new strategies for neonatal neuroprotection. Our multi-disciplinary team is comprised of neonatologists, neurologists, pharmacists, students (high school, undergraduate and medical) and research support staff.

Currently we use large multimodality (NIRS, EEG, MRI) datasets to develop new approaches to understanding the pathophysiology of both preterm (intraventricular hemorrhage, white matter injury) and term (hypoxic-ischemic encephalopathy) forms of brain injury, as well as seizures in all neonates. We continue to recruit new patients for observational and clinical trials. 

Birth defects affect approximately 3% of U.S. infants and are a major cause of morbidity and mortality. Despite their prevalence, little is known about their causes. To discover genomic variants associated with rare, diagnostically challenging birth defects in newborn infants and children, we use next generation sequencing (exome or whole genome sequencing) of affected infant/parent trios. We computationally identify rare variants (minor allele frequency less than 0.01) and predict function with a suite of algorithms that incorporate evolutionary conservation and known regulatory motifs. To prove causality of discovered variants, we use model systems (worms, fruit flies, zebrafish, mice) to demonstrate function of discovered variants, and replication of candidate gene loci or pathways in unrelated infants with similar phenotypes.

Genetic regulation of neonatal pulmonary surfactant deficiency has been suggested by studies of gender, genetic linkage, recurrent familial cases, gene knockout models in mice and by racial disparity in risk of neonatal respiratory distress syndrome. Successful fetal-neonatal pulmonary transition requires production of the pulmonary surfactant, a phospholipid-protein film that lines alveoli and maintains alveolar patency at end expiration. Our goals are to understand the genetic mechanisms that disrupt pulmonary surfactant metabolism and cause neonatal respiratory distress syndrome as well as to understand the implications of these genetic mechanisms on the development of interstitial lung disease and pulmonary fibrosis.

To discover genomic variants associated with neonatal respiratory distress syndrome and childhood interstitial lung diseases, we use candidate gene-focused (multiplexed direct genomic selection) and unbiased (exome sequencing and whole genome sequencing) next generation sequencing strategies and advanced computational quality, coverage and filtering methods. To predict function of discovered variants, we use a suite of algorithms that incorporate evolutionary conservation and known regulatory motifs. Finally, we use human cell culture model systems to test biologic function of discovered variants.

WashU is one of five clinical sites of the National Heart, Lung, and Blood Institute sponsored Prematurity–Related Ventilatory Control (Pre-Vent): Role in Respiratory Outcomes and Respiratory Outcomes Program. The objective of the program is to investigate mechanisms of ventilatory control (e.g. chemoreceptor, mechanoreceptor, developmental, etc.) that contribute to instability of oxygenation and risk of morbidity and mortality in premature infants during and after the Neonatal Intensive Care Unit (NICU) using a prospective observational cohort.

The Washington University site is investigating novel techniques for calculation of loop gain of the respiratory system and explore the links between abnormalities seen by magnetic resonance imaging (MRI) and aberrant ventilatory control. The proposed studies are designed to help clarify the indications for airflow support, supplemental oxygen therapy and a ventilatory stimulant (caffeine) as these infants grow and mature.

Intestinal Microbiota

• The development of the intestinal microbiome and its contribution to NEC and preterm morbidities (Tarr lab)
• The development of intestinal microbiome and antibiotic resistance (Dantas lab)
• Defining the virome of healthy and diseased infants (Holtz lab)
• The ecology of the intestinal microbiome during early development

Ecology of the intestinal microbiome during early development

The St. Louis Neonatal Gut Microbiome Initiative utilizes a local birth cohort of health twins to examine the impact of genetics, diet and environment on development of the intestinal microbiome during early development. Additional collaborations utilizing this cohort include:

• Jeffrey Gordon and the Center for Genome Sciences & Systems Biology examine geographic differences as it relates to nutrition and health.

Barbara Warner, MD
Phillip Tarr, MD

Intestinal microbiome & necrotizing enterocolitis

As part of the NIH Human Microbiome project (P.I. Tarr), we are examining the ecology of the intestinal microbiome in a preterm population within an NICU environment, identifying host and environmental factors impacting its development and the role in health and disease. This includes necrotizing enterocolitis as well as other morbidities such as late onset sepsis, chronic lung disease and neurologic development.

Phil Tarr, MD
Barbara Warner, MD

Intestinal microbiome & antibiotic resistance

In collaboration with the Dantas laboratory within the Center for Genome Sciences, we are examining the role of the neonatal intestinal microbiome as a reservoir of antibiotic resistance genes, and determining social and environmental factors, such as antibiotic exposure and diet, in their origin and transmission.