The goal of my research program is to identify the genetic mechanisms that direct lung and pulmonary vascular development and physiological adaptation to birth. As a neonatologist I take care of many infants who are born prematurely or who have anomalies that impair lung or pulmonary vascular development and function. Among the most challenging of these patients are infants born with congenital diaphragmatic hernia (CDH). CDH is one of the most common and most severe of all congenital malformations with a frequency of 1 in 3500 live births and a mortality rate of 20-50%. Babies with CDH have a hole in the diaphragm that allows the abdominal organs to herniate into the chest. Although surgical repair of the diaphragm can move the abdominal organs out of the thorax and provide room for the lungs to inflate, the lungs and pulmonary vasculature often do not develop or function normally. As a result, many infants with CDH do not survive after birth due to lung hypoplasia and severe pulmonary hypertension.
During my fellowship at the University of California, San Francisco I was mentored by Dr. Brian Black in the Cardiovascular Research Institute where I learned to use genetic tools to investigate cardiovascular development in mice. After moving to the University of Wisconsin-Madison, I was mentored by Dr. Xin Sun and applied the approaches I learned to study the developing lungs and pulmonary vasculature. Recently I have focused on identifying the genetic mechanisms responsible for lung and pulmonary vascular defects associated with CDH. Despite the frequency and severity of CDH, the genetic cause of the malformation and the mechanisms that lead to abnormal development and function of the lungs and pulmonary vasculature are poorly understood.
In my recent work, I have used a combination of state-of-the-art genetic gain-of-function and loss-of-function experiments, in vivo physiology, and 2- and 3-dimensional histology to identify the genetic mechanisms responsible for abnormal lung and pulmonary vascular development associated with CDH. To conduct this research, I collaborate with human geneticists who are conducting whole genome sequencing in patients with CDH. Using the results of these sequencing studies, I have generated new mouse models of CDH to identify the mechanisms of abnormal lung and pulmonary vascular development. I also collaborate with lung and pulmonary vascular physiologists to determine the functional consequences of the genetic mutations we have identified in human patients.
My long-term goal is to continue investigating the basic mechanisms of lung and pulmonary vascular development related to CDH and preterm birth. By identifying the underlying mechanisms of abnormal development, I hope to identify new therapeutic approaches that improve fetal and early postnatal lung development and function in pediatric patients. I plan to build a translational research program where our genetic mechanism studies will be used to devise novel and precise therapy for patients based on their individual genetic defect(s). I plan to carry out this work while serving as a mentor for both clinical and basic science research trainees who are pursuing careers in basic and translational biomedical research.
The Midwest Society for Pediatric Research (MSPR) held its annual meeting at Lurie Children’s Hospital last week and the UW-Madison Department of Pediatrics was well represented. Members from all levels of the UW-Madison Department of …October 30, 2019
Lectures by the 2018 and 2019 Gerard B. Odell Research Award winners, along with rows of research posters filling the Health Sciences Learning Center (HSLC) were among the highlights of the Department of Pediatrics’ 2019 …June 5, 2019
David McCulley, MD (Assistant Professor, Division of Neonatology & Newborn Nursery), received his first R01 award from the National Institutes of Health National Heart, Lung, and Blood Institute for his project, “Genetic and Developmental Mechanisms of …May 1, 2019
In 2018, five Department of Pediatrics faculty members were accepted as members of the Society for Pediatric Research (SPR). SPR’s mission is to create a network of multidisciplinary researchers to improve child health. Specifically, it …January 1, 2019
Two Department of Pediatrics faculty – Christian Capitini, MD (Assistant Professor, Division of Hematology, Oncology and Bone Marrow Transplant) and David McCulley, MD (Assistant Professor, Division of Neonatology and Newborn Nursery) – have been named …January 1, 2019
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