Venkatesh Sampath, MBBS, MRCPCH

Sosland Endowed Chair in Neonatal Research; Director, Neonatal Diseases Research Program; Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Research Associate Professor of Pediatrics, University of Kansas School of Medicine

Full Biography

Venkatesh Sampath, MBBS, MRCPCh, Neonatologist, Sosland Endowed Chair of Neonatology Research and Medical Director of the Neonatal Diseases Research Program at Children’s Mercy Kansas City, has received a $2.3 million R01 grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) under award number 1R01HL162937.

This funding will support the study of how delta like 4 (DLL4), a molecule expressed in endothelial cells, regulates blood vessel and air sac formation during normal and abnormal (bronchopulmonary dysplasia) lung development and may help identify new therapies for BPD.

Dr. Sampath will serve as Principal Investigator for this study titled “DLL4 in the Developing Lung and Bronchopulmonary Dysplasia (BPD)”. Co-investigators for the study include Elin Grundberg, PhD, Children’s Mercy; Jichao Chen, PhD, MD Anderston Institute; and Ramani Ramchandran, PhD, Medical College of Wisconsin. Dr. Donald DeFranco, University of Pittsburgh School of Medicine, will serve as a consultant, and Janelle Noel-MacDonnell, PhD, Children’s Mercy, will provide statistical support.

The Children’s Mercy Neonatal Diseases Research team will perform experiments for this grant. They include Sheng Xia, PhD; Heather Menden, MS; Sherry Mabry, MS; Aparna Venkatraman, PhD; Wei Yu, PhD; and Mariane Nsumu, MS.

Why is this research important?

BPD is a serious lung condition that most often affects babies born more than 10 weeks before their due date and who weigh less than 2.2 pounds (1,000 grams). This often results in breathing problems at birth and the need for long-term breathing support and oxygen.¹

Scientifically, BPD is characterized by abnormalities in blood vessel and air sac development. However, how endothelial cells (EC) regulate formation of blood vessels and air sacs during lung development, and how this is disrupted in infants with BPD is not fully understood.

According to Dr. Sampath, at any one time, approximately 20% of the patients hospitalized in the Children’s Mercy Level IV Neonatal Intensive Care Unit (NICU) are diagnosed with BPD, as are 10,000-15,000 neonates born in the U.S. each year.

“Infants born weighing less than 1,000 grams are at greatest risk for developing BPD, and complications of the disorder make it important to understand the science behind why it develops, how it affects them, and what research can do to help,” Dr. Sampath explained.

In addition, the number of cases of BPD has been increasing in recent years, most likely because of modern advances in medicine, which have enabled doctors to keep more very low birth weight, premature babies alive than in the past.¹

Previously, Dr. Sampath published his research on DLL4 in JCI Insight in 2021. In that article he noted mammalian lung development progresses sequentially, with formation of the tiny air exchange units, called alveoli, happening after birth. In preterm infants, exposure to noxious stimuli such as infection, mechanical ventilation and hyperoxia injure lung blood vessels, disrupting formation of alveoli and resulting in BPD. ^2,3,4,5

This was the first study to demonstrate that endothelial (EC) DLL4 regulates microvascular growth and arborization during distal lung ontogeny and Dll4 deficiency programs deviant angiogenesis, disrupting lung vascular patterning and alveolarization. These phenotypic changes occurred concurrently with altered expression signatures of lung endothelial cell fate specification and notch signaling, as well as impaired expression of AT1 lineage markers.⁶

What does this grant involve?

In this four-year NIH grant, Dr. Sampath and his colleagues will test the hypothesis that DLL4 regulates development of CAR4+ endothelial cells (a specialized type of endothelial cells that extract oxygen from the lung) and alveolar type I cell (that are critical for lung gas exchange, AT1) development during distal lung morphogenesis, and disruption of endothelial DLL4 signaling in hyperoxia programs vascular and alveolar defects in BPD.

They will do this by studying how EC-Dll4 deletion in sequential lung stages reprograms lung EC fate, heterogeneity and the CAR4+ EC population. Cell autonomous regulation of CAR4+ fate and angiogenesis by DLL4 will be probed in primary and Dll4-deficient HPMEC lines created in the Neonatal Research Lab.

The researchers also will investigate the regulation of AT1 development/function and alveolarization by EC DLL4. They will use single-cell RNA sequencing to identify the EC ligand - AT1 receptor interactions and AT1 molecular pathways disrupted with EC Dll4 deletion. In addition, they will study whether Dll4 loss disrupts EC angiocrine signaling through hepatocyte growth factor.

And finally, they will combine molecular phenotyping of autopsy samples with human BPD samples with studies in Dll4EC -/- vs. +/- vs. +/+ mice to determine EC-Dll4’s role in disrupting EC fate, AT1 ontogeny and lung morphogenesis in the hyperoxia-model of experimental BPD. The exciting and translational aspect of this study is that they will test the efficacy and therapeutic mechanism by which ciclesonide rescues DLL4 signaling. Lung injury in HOX also will be tested.

Ciclesonide is a synthetic steroid such as those used for asthma that works by preventing inflammation in the lungs, and is already FDA-approved to treat asthma in children 5 and up. Dr. Sampath and his colleagues have shown that in mice and rats that ciclesonide is less neurotoxic than dexamethasone, which is currently used to prevent BPD in premature neonates. The investigative team seeks to establish that ciclesonide is as efficacious in preventing BPD in premature neonates, while being less harmful to the brain.

What is the potential long-term impact?

This research impacts the field of neonatology and the care of neonates by attempting to discover DLL4’s role in lung EC fate specification and AT1 ontogeny using innovative strategies. The significance lies in addressing critical barriers underpinning the vascular origins of BPD and the resulting translational potential. Plus, the researchers will study DLL4’s role in BPD, and will test the efficacy of ciclesonide to rescue DLL4 signaling, mitigating BPD in a pre-clinical model.

“This research is an important step toward helping us understand the basic science behind BPD,” Dr. Sampath said. “Our hope is that in the next decade, we will be able to identify those neonates most at risk for BPD, and develop a more effective therapy to protect them from lung injury while mitigating treatment side effects.

“In addition, we are exploring the translational significance of ciclesonide in a proposed Phase 1 safety study of this medication in preterm infants,” he added. “Our goal in this separate study is to conduct a large therapeutic trial to determine whether ciclesonide can more safely prevent BPD in neonates.”

Related Research

The Children’s Mercy Neonatology team is very active in research and has published several basic science and clinical research papers on neonatal lung disease recently including:

• Xia S, Menden H, Townley N, Mabry SM, Johnston J, Nyp MF, Heruth DP, Korfhagen T, Sampath V. Delta like 4 is required for pulmonary vascular arborization and alveolarization in the developing lung. JCI Insight. 2021;6(7):e134170. https://doi.org/10.1172/jci.insight.134170.
• Salimi U, Dummula K, Tucker MH, Dela Cruz CS, Sampath V. Postnatal Sepsis and Bronchopulmonary Dysplasia in Premature Infants: Mechanistic Insights into "New BPD". Am J Respir Cell Mol Biol. 2022 Feb;66(2):137-145. doi: 10.1165/rcmb.2021-0353PS. PMID: 34644520; PMCID: PMC8845139.
• Akangire G, Lachica C, Noel-MacDonnell J, Begley A, Sampath V, Truog W, Manimtim W. Outcomes of infants with severe bronchopulmonary dysplasia who received tracheostomy and home ventilation. Pediatr Pulmonol. 2022 Nov 14. doi: 10.1002/ppul.26248. Epub ahead of print. PMID: 36377273.
• Tucker MH, Yeh HW, Oh D, Shaw N, Kumar N, Sampath V. Preterm sepsis is associated with acute lung injury as measured by pulmonary severity score. Pediatr Res. 2022 Jul 29. doi: 10.1038/s41390-022-02218-1. Epub ahead of print. PMID: 35906303.
• Xia S, Vila Ellis L, Winkley K, Menden H, Mabry SM, Venkatraman A, Louiselle D, Gibson M, Grundberg E, Chen J, Sampath V. Neonatal hyperoxia induces activated pulmonary cellular states and sex-dependent transcriptomic changes in a model of experimental bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. 2022 Dec 20. doi: 10.1152/ajplung.00252.2022. Epub ahead of print. PMID: 36537711.

Dr. Sampath’s research is supported by NHLBI, NIDDK, NICHD, the Department of Pediatrics/Neonatology and the Children’s Mercy Research Institute.

References

1. National Organization for Rare Disorders (NORD) website: rarediseases.org/ are-diseases/bronchopulmonary-dysplasia-bpd/. Accessed March 22,2021.
2. Bancalari E JA. NICHD / NHLBI / ORD Workshop Summary - Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2001;163:1723–1729.
3. Morty RE. Recent advances in the pathogenesis of BPD. Semin Perinatol. 2018;42(7):404–412.
4. Menden HL, Xia S, Mabry SM, Navarro A, Nyp MF, Sampath V. Nicotinamide adenine dinucleotide phosphate oxidase 2 regulates LPS-induced inflammation and alveolar remodeling in the developing lung. Am J Respir Cell Mol Biol. 2016 Dec;55(6):767-778. doi: 10.1165/rcmb.2016-0006OC. PMID: 27438994; PMCID: PMC5248953.
5. Menden H, Xia S, Mabry SM, Noel-MacDonnell J, Rajasingh J, Ye SQ, Sampath V. Histone deacetylase 6 regulates endothelial MyD88-dependent canonical TLR signaling, lung inflammation, and alveolar remodeling in the developing lung. Am J Physiol Lung Cell Mol Physiol. 2019 Sep 1;317(3):L332-L346. doi: 10.1152/ajplung.00247.2018. Epub 2019 Jul 3. PMID: 31268348; PMCID: PMC6766719.
6. Xia S, Menden H, Townley N, Mabry SM, Johnston J, Nyp MF, Heruth DP, Korfhagen T, Sampath V. Delta like 4 is required for pulmonary vascular arborization and alveolarization in the developing lung. JCI Insight. 2021;6(7):e134170. https://doi.org/10.1172/jci.insight.134170.

The contents are those of the investigator and do not necessarily represent the official views of, nor an endorsement, by NIH, or the U.S. Government.