Newborn Medicine

• Understand the role of a gene called cofilin-2 (CFL2) in the regulation of actin, a component of skeletal muscle thin filament. To understand this, he is creating a mouse model of cofilin-2 knockout. In addition, he plans to make a knockin of a missense cofilin-2 mutation that he recently identified in a consanguineous family of nemaline myopathy.
• Study the gene called selenoprotein N (SEPN1), mutations of which cause various congenital myopathies. The function of selenoprotein N is unknown. He is evaluating the gene expression profile of muscles from patients with SEPN1 mutation and comparing them with normal to get functional clues.

Ultimately, Dr. Agrawal's research will help decipher the molecular mechanisms of skeletal muscle functioning, and in the future help diagnose and treat patients with congenital muscle disorders.

• Determine whether the Neonatal Resuscitation Program is effective at teaching resuscitation skills.
• Assess the effectiveness of teaching the differential diagnosis of respiratory distress to medical students using standard methods compared with simulator-based training.

By examining the short- and long-term effects of simulator-based training, Dr. Brodsky hopes to demonstrate the benefit of simulator training, with the ultimate goal of incorporating simulation into the newborn medicine curriculum of trainees at multiple levels.

• Understand the role of papain-like cysteine proteases and their inhibitors in the development of neonatal lung injury and repair. These proteases interact with extracellular matrix proteins that are critical in the process of alveolarization, a key event that is disrupted in CLD.
• Elucidate mechanisms that regulate fibroblast proliferation and distribution in neonatal lung injury.

These investigations should enhance our understanding of the pathogenesis of CLD and facilitate development of novel preventive and therapeutic interventions for this disease.

• Define the molecular mechanisms underlying regulation of gene expression by extracellular acidosis in vascular cells.
• Examine the functional significance of acidosis-induced changes in gene expression in vascular cells.
• Determine the in vivo effects of extracellular acidosis in a model of lung ischemia-reperfusion injury.

Ultimately, Dr. Christou's research may identify specific molecular targets for therapies for disorders in which acidosis may play a pathogenetic or protective role.

• With clinical research plagued by inconsistent results, Dr. Dwyer designs statistical software that uses algorithms to score randomization schemes for randomized clinical trials (RCTs). Often overlooked until an RCT nears completion, imbalances in the predictors of outcome impact RCTs, and at lower levels than previously thought.
• Without accurate measurements of nasopharyngeal pressure in High-Flow Nasal Cannula (HFNC) systems, neonates have an increased risk of pneumothorax as well as haphazard respiratory stability, often requiring additional time on conventional mechanical ventilation and/or continuous positive airway pressure (CPAP). Dr. Dwyer's lab developed a method to obtain accurate noninvasive nasopharyngeal pressures using a modified heated and humidified HFNC system.

The goals of his work are to:

• Compare the impact of heterogenous covariates (preditors of outcome), sample size, number of trials centers, and type of randomization scheme with respect to a unified scoring system.
• Demonstrate the safety and accuracy of this HFNC system, as well as the ability to assess multiple predictors of nasopharyngeal pressure in neonates.

• Statistical planning software shows that significant decreases in under- or overstating treatment effects can be achieved efficiently, allowing decreased time needed for post-RCT analysis, as well as increased likelihood of FDA approval.
• Safe and accurate HFNC systems may decrease the incidence of pneumothoraces, the need for mechanical ventilation/CPAP, and the discomfort and trauma associated with other modalities. The methodology is applicable to other medical domains: burn patients, facial trauma, etc.

Dr. Dwyer is in the process of obtaining patents for both of these projects.

• Understand better the pathobiology of pulmonary hypertension (PHtn) and the molecular mechanisms of developmental lung injury and repair leading to bronchopulmonary dysplasia (BPD). Studies in animal physiology and basic molecular biology are validated with studies in infants with lung disease using patient-derived material. Linked to this work are genomic approaches to identify genetic markers of predisposition to BPD and PHtn.
• Ongoing work in the laboratory also explores the role of mesenchymal stem cells (MSC) in the prevention and treatment of lung disorders that affect neonates and children. Dr. Kourembanas has demonstrated both prevention and reversal of lung vascular disease, and is actively pursuing molecular and cellular mechanisms of action.

Ultimately, Dr. Kourembanas' research may identify specific molecular targets for therapies of lung diseases, both to prevent and to reverse established injury.

• Develop experimental tools to study cell fate specification in the pre-implantation mouse embryo.
• Develop defined culture conditions for deriving human embryonic stem cells (hESC).
• Derive hESCs using nuclear transfer.

Ultimately, Dr. Lerou's research hopes to lay the groundwork for combined genetic and cell based therapies.

• Understand the pathophysiologic mechanisms that lead to predisposition and development of chronic lung disease in premature newborns.
• Develop optimal clinical strategies for prevention and treatment of chronic lung disease.
• Evaluate the therapeutic potential for the antioxidant, SOD, for the prevention of chronic lung disease, retinopathy of prematurity, and neurologic injury.
• Optimize strategies for newborn screening for cystic fibrosis.

Ultimately, Dr. Parad's research may protect premature newborn lungs from injury and optimize their pulmonary outcomes; and improve outcomes in cystic fibrosis.

• Conduct biochemical analyses of GPR56 and its signaling pathways.
• Characterize the GPR56 function in mouse models.

Ultimately, Dr. Piao's research may delineate a novel signaling pathway in normal brain development and malformation.

• The overall goal of her basic research is to determine how GBS transition from harmless commensal organisms to invasive pathogens. The specific aims of her research are to determine how GBS respond to changes in environmental temperature and pH, and to antibiotic exposure, by studying the global transcriptional responses to such changes mediated by two-component regulatory systems.
• The overall goals of her clinical research are to evaluate the impact of intrapartum antibiotic prophylaxis for neonatal GBS disease on the incidence and microbiology of early-onset sepsis; and to determine the clinical and microbiological factors mediating methicillin-resistant and methicillin-sensitive Staphylococcus aureus colonization and infection in the neonatal intensive care unit.

Ultimately, Dr. Puopolo's basic research may identify specific GBS virulence factors that can be used in the development of new approaches to the prevention and treatment of gram-positive bacterial infections. Her clinical research may identify factors associated with neonatal sepsis that can be used to devise clinical strategies for the prevention of such infections.

• Determine the roles and mechanisms of action of chemokine receptors and immunoglobulin receptors in host defense against Pseudomonas and RSV pneumonia.
• Define risk factors for pulmonary hypertension in patients with chronic lung disease of prematurity, and determine the significance of pulmonary hypertension in long-term pulmonary morbidities in premature infants.

Ultimately, Dr. Rhein's research hopes to identify specific molecular targets that could lead to therapies for pulmonary infectious or inflammatory diseases. His research also hopes to determine which premature infants will require evaluation or therapy for pulmonary hypertension.

• Understand why some preterm infants and their families do well after discharge from the NICU and others do not.

Ultimately, the goal of Dr. Smith's research is to create interventions to improve outcomes for all preterm infants and their families.

• Advance scientific understanding of the interaction of epidemiologic exposures of these two important neonatal cardiopulmonary disorders.
• Identify preventable exposures that will prevent or ameliorate the risk of BPD and/or PPHN.

• Perform and improve the validity of economic evaluations alongside neonatal clinical trials. A systematic review of the neonatal literature showed that fewer than 1% of randomized controlled trials have associated economic evaluations, and that the methodological quality of those performed is poor (Pediatric Research. 2001; 49(4): 364A.). Economic evaluations currently underway by Dr. Zupancic and colleagues alongside multi-center clinical trials include (i) high versus low red blood cell transfusion thresholds for newborns; (ii) drug therapy for prevention of neonatal chronic lung disease; (iii) high versus low oxygen saturation thresholds for the prevention of retinopathy of prematurity; (iv) intermittent nasal ventilation for the reduction of chronic lung disease in premature infants; and (v) peer support for post-prevention of post-partum depression.
• Perform computer modeling to determine best practice when evidence is currently lacking or where empirical studies are infeasible. Most recently, this has focused on the use of discrete event simulation to assess the impact of diffusion and regionalization on the cost and efficacy of new device technologies.