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Marshall Klaus Perinatal Research Awards

Klaus Awardees Research Projects

The American Academy of Pediatrics (AAP), the Section on Perinatal Pediatrics, and Johnson & Johnson Pediatric Institute initiated the Marshall Klaus Perinatal Research Awards with the goal of enhancing and supporting development of research skills among physicians training in Neonatal-Perinatal Medicine. These awards provide partial support intended to assist fellows in initiating or completing research projects. Grants of $5,000/year are available.

Klaus Awards 2014

Sundeepta Kumar Basu, MD

Mentor: Bhagavatula Moorthy, MD
Baylor College of Medicine

Molecular regulation of human cytochrome P4501A1 gene by hyperoxia in human lung cells: implications for bronchopulmonary dysplasia

Dr. Basu’s research is based on the hypothesis that cytochrome P4501A1(CYP1A1) is a previously unrecognized novel endogenous anti-oxidant which plays a protective role against hyperoxic lung injury. Oxygen mediated lung injury plays central role in pathogenesis of bronchopulmonary dysplasia (BPD) which is a major healthcare burden in premature infants with high mortality and morbidity. CYP1A1 is involved in metabolism of reactive oxygen species (ROS) and in animal studies have demonstrated lung protective effect. Dr. Basu’s work under Dr. Moorthy’s mentorship is dedicated to understanding the molecular regulation of CYP1A1 expression on exposure to oxygen. While CYP1A1 regulation has been historically described by arylhydrocarbon receptor pathway, very little is known about regulation mechanisms in response to hyperoxia. Dr. Basu is using human lung cells (H441) to identify the regulatory steps of CYP1A1, which may guide pioneering interventions with tremendous scope in prevention and/or management of hyperoxic lung injury and BPD in
premature infants.

Andrew Dylag , MD

Mentor: Richard Martin, MD
Case Western Reserve University

Long term airway hyperreactivity following neonatal chronic intermittent hypoxia with hyperoxia

Physicians in the Neonatal Intensive Care Unit are challenged with maintaining adequate levels of oxygen (O2) saturation. Recurrent apnea and respiratory insufficiency associated with apnea of prematurity leads to frequent episodes of O2 desaturation despite supplemental O2 therapy. The incidence of desaturations (<80% saturation for 10-180 seconds) increases dramatically during the first 4 postnatal weeks, and extremely preterm infants can experience over 600 desaturation events in a one-week period. In the clinical setting, these events are either self-limited or resolved by a transient increase in the fraction of inspired oxygen (FIO2), most commonly titrated by the bedside nurse. A consequence of increasing FIO2 to resolve the desaturation event; however, is an ensuing overshoot and a transient period of relative hyperoxia.They have developed a novel model of neonatal mouse chronic intermittent O2 exposure with hyperoxia overshoots to determine their synergistic effects on airway hyper-reactivity mechanisms. The purpose of this study is to investigate whether neonatal chronic intermittent hypoxia super-imposed with intermittent hyperoxia causes a long-term synergistic increase in airway reactivity associated with airway smooth muscle proliferation and increased airway BDNF expression in neonatal mice.

Vikramaditya Dumpa, MD

Mentor: Vasanth Kumar
State University of New York at Buffalo

Effects of caffeine on angiogenesis and alveolarization in newborn mice with hyperoxic lung injury

Caffeine therapy has been shown to decrease the incidence of bronchopulmonary dysplasia in preterm infants. The molecular mechanisms underlying this action of caffeine are uncertain. Hypoxia inducible factors (HIF) are transcription factors that regulate the expression of genes encoding the vascular development. We hypothesize that caffeine modulates the expression of HIF, which affects angiogenesis in newborn mice model exposed to hyperoxia or hypoxia. We plan to assess the expression of HIF subunits, the angiogenic target genes and their receptors after the mice are injected with caffeine. We also plan to measure the inflammatory and anti-inflammatory cytokines following caffeine exposure to determine whether the protective effects are by modulating inflammation. This research project is likely to contribute to better understanding of the role of caffeine in modulating HIF expression and its effects on vascular development.

Rachel Heilman, MD

Mentor: Kathryn Farrow, MD
Northwestern University

The role of PDE5 in the right ventricle in mice with hyperoxia-induced pulmonary hypertension

Dr. Heilman’s research focuses on investigating the molecular mechanisms and pathophysiology leading to the development of right ventricle hypertrophy (RVH) and right ventricular failure in the context of bronchopulmonary dysplasia (BPD) associated pulmonary hypertension. Under the mentorship of Dr. Kathryn Farrow, Dr. Heilman became interested in the role of phosphodiesterases (PDE) and cyclic-guanosine monophosphate (cGMP) signaling in the right ventricle of the heart. While this pathway has recently been implicated in adult models of heart failure, it has never been investigated in neonatal heart failure. In the proposed project, Dr. Heilman will investigate the role of PDE5 in the right ventricle in the BPD-associated pulmonary hypertension mouse model. She has hypothesized that hyperoxia exposure increases reactive oxygen species, which in turn disrupts the cGMP signaling pathway in neonatal cardiomyocytes leading to upregulation of cardiac PDE5, RVH, and right ventricle dysfunction. Using the BPD-associated pulmonary hypertension mouse model with genetically altered mice as well as in vitro experiments on isolated neonatal mouse cardiomyocytes, Dr. Heilman hopes to better understand the changes in the RV and the neonatal cardiomyocytes in the BPD-associated pulmonary hypertension that precede RVH and RV failure and the relationship of RVH to increased afterload associated with pulmonary vascular remodeling

Thomas Hooven, MD

Mentor: Adam Ratner, MD

The role of environmental arginine sensing in the pathogenesis of perinatal group B streptococcus infection.

Dr. Hooven’s work explores how micronutrient sensing by Group B treptococcus (GBS) affects expression of virulence factors that contribute to perinatal infection. Dr. Hooven is using a novel murine model of GBS ascending chorioamnionitis to investigate how environmental amino acid concentrations affect expression of beta-hemolysin/cytolysin, a GBS small molecule cytotoxin that contributes to preterm birth and fetal injury. Changes in the chemical milieu of the reproductive tract during late pregnancy may trigger micronutrient-mediated transcriptional changes that cause GBS to produce more beta-hemolysin/cytolysin, leading to invasion. His proposed experiments combine classical microbiological techniques with more recent forms of analysis, including next generation sequencing, to screen the GBS genome for regions whose transcription is affected by environmental micronutrients. He hypothesizes that GBS senses the concentration of certain environmental amino acids, and that in most strains physiologic concentrations—indicative of nutritive surroundings—down regulate virulence factor production that would promote bacterial invasion and escape from a nutrient-poor environment. Conversely, low amino acid levels may be associated with an up regulation of virulence factor production. Furthermore, certain highly virulent strains of GBS may carry mutations that interfere with micronutrient sensing and lead to increased pathogenicity.Understanding the interplay between micronutrient concentrations and virulence factor expression may yield new pharmacologic approaches to preventing and treating serious perinatal GBS infections.

Tarek Mohamed , MD

Mentor: Bruce Uhal, PhD
Michigan State University

Hypoxia upregulates angiotensin converting enzyme-2 (Ace-2) in fetal neonatal and adult lung cells

Dr. Mohamed's area of interest is lung physiology in chronic lung disease (CLD). His main question was does chronic lung injury occur mainly because of exposure of alveoli to high oxygen -as many studies have shown- or could it be exposure to hypoxia or even anoxia in some lung foci that may cause similar damage and CLD. He always wondered how the fetal lung cells survive while exposed to physiologic hypoxia while in utero yet do not even have any immediate sequelae after birth; i.e., is there a protective mechanism which protects fetal lung cells from CLD? He hoped that understanding this transition and reaction to hypoxia could help us to better understand CLD and help to develop a better way of preventing and treating CLD.

Dr. Mohamed is fortunate to work with Dr. Bruce Uhal, whose lab has shown that during lung injury, the vasoactive peptide angiotensin II, independent of the "endocrine" renin-angiotensin system, induces collagen deposition and fibrosis, which eventually leads to abnormal restructuring of the lung architecture.

Dr. Mohamed's initial working hypothesis was that angiotensin converting enzyme (ACE-2) might be up- regulated in fetal lung fibroblasts exposed to hypoxia (simulating the physiologic fetal hypoxemia), which could in turn protect fetal lungs from undergoing fibrotic changes in response to hypoxemia. This may be germane in adult lung disease, as well, since "protective" ACE-2 levels may decline with age, thus explaining why the elderly are more at risk for lung fibrosis. Using the fetal lung fibroblast IMR-90 cell line, Dr. Mohamed's work will assay ACE-2 levels, enzymatic activity, and biochemical markers of fibrogenesis.

Eric Peeples , MD

Mentors: Sandra Juul, MD
University of Washington

Fast Doppler assessment of cerebral perfusion in preterm infants

Impaired cerebral perfusion contributes to significant morbidity in preterm infants. Currently available ultrasonographic methods of evaluating cerebral blood flow are limited to assessing large blood vessels, while many of the changes in the cerebral vasculature of premature infants may occur only in smaller vessels. Fast Doppler ultrasound has the ability to acquire Doppler images that are sufficiently fast and spatially dense to identify tissue- level blood flow within the brain. 

2013 Marshall Klaus Research Awardees »

Past Marshall Klaus Research Awardees»

Complete List of Awardees and Mentors »

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