Omics of Lung Development and Disease

Dr. Yan Xu, PhD, leads a team of bioinformatician, computer scientists and biologists with a mission to use transcriptomics, proteomics and lipidomics to understand lung development and disease. Dr. Minzhe Guo developed new computer programs to handle and display large datasets from single cell RNA sequence data. With Dr. Yan Xu, he developed the code for “Sincera” and “SLICE” to enable the field to use big data from single cell RNA studies of developing lung to understand the cellular and molecular mechanisms that instruct the formation of the organ. “SLICE”, based on a calculation of entropy, predicts cell lineages and fate decisions regulating organ formation: Guo M, Bao E, Wagner M, Whitsett JA, Xu Y. SLICE: determining cell differentiation and lineage based on single cell entropy. Nucleic Acids Res. 2016 Apr 20;45(7):e54.

Ms. Yina Du developed Lung Gene Expression Atlas (LGEA), a web tool that displays big data enabling rapid search of cells, genes, RNAs, and proteins: Du Y, Kitzmiller JA, Sridharan A, Perl AK, Bridges JP, Misra RS, Pryhuber GS, Mariani TJ, Bhattacharya S, Guo M, Potter SS, Dexheimer P, Aronow B, Jobe AH, Whitsett JA, Xu Y. Lung Gene Expression Analysis (LGEA): an integrative web portal for comprehensive gene expression data analysis in lung development. Thorax. 2017 May;72(5):481-84. Dr. Yan Xu, and her team, use these tools to explore the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF) an enigmatic, lethal chronic lung disease. Her work provides new insights into the cellular and molecular processes causing the loss of tissue and respiratory failure in this disorder: Xu Y, Mizuno T, Sridharan A, Du Y, Guo M, Tang J, Wikenheiser-Brokamp KA, Perl A-KT, Funari VA, Gokey JJ, Stripp BR, Whitsett JA. Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis. JCI Insight. 2016 Dec 8:1(20):e90558. The application of systems biology to the ever expanding “omic” data provides new opportunities to uncover the mysteries of organ formation during normal development from which to explore the cellular and molecular causes of diseases that are presently considered “idiopathic”.

Understanding Rare Lung Disease in Newborns – Alveolar Capillary Dysplasia

Dr. Vladimir Kalinichenko, MD, PhD, leads a team of scientist seeking to understand the causes and mechanisms underlying the pathogenesis if ACD, a rare but devastating lung disease affecting newborn infants. Infants with ACD suffer respiratory failure and hypoxemia, and usually die soon after birth despite of intensive care. Mutations cause most ACD in the gene FOXF1. Dr. Kalinichenko developed transgenic mouse models by inserting mutations in the FOXF/gene. His work shows the critical role of FOXF1 in directing lung vascular development before birth, and its role in maintaining the pulmonary microvasculature critical for lung function after birth. His team is uncovering the genetic networks directed by FOXF1 developing new approaches to enhance FOXF1 activity for therapy of ACD and other lung diseases: Dharmadhikari AV, Szafranski P, Kalinichenko VV, Stankiewicz P. Genomic and epigenetic complexity of the FOXF1 locus in 16q24.1: Implications for development and disease. Curr Genomics. 2015 Apr;16(2):107-16.

*Cai Y, Bolte C, Le T, Goda C, Xu Y, Kalin TV, Kalinichenko VV. FOXF1 maintains endothelial barrier function and prevents edema after lung injury. Science Signaling. 2016 Apr 19; 9(424):ra40. *This paper is on the cover page of Science Signaling, April 19, 2016 issue.

Elucidation of the Gut-Lung Axis in Innate Defense of the Neonatal Lung

Newborn preterm infants are highly susceptible to bacterial pneumonia, a major cause of infant mortality worldwide. Dr. Hitesh Deshmukh, MD, PhD, and his team, have uncovered a novel pathway by which the colonization of the GI tract with normal bacterial flora after birth is required for the development of innate defenses of the lung to fight bacterial infection. His work in Science Translational Medicine (Gray J, Oehrle K, Worthen G, Alenghat T, Whitsett J, Deshmukh H. Intestinal commensal bacteria mediate lung mucosal immunity and promote resistance of newborn mice to infection. Sci Transl Med. 2017 Feb 8;9(376)) demonstrates lack of gut bacteria, caused by administration of antibiotics before birth blocks signals required for recruitment and expansion of specialized innate lymphocytes (ILC3 cells) to the lung, where they activate defenses against bacterial pneumonia. He found that the ILC3 precursors traffic to the lung and secrete IL-22 that enhances resistance to pneumonia, and that this “trafficking” requires normal gut bacterial flora. Mothers, and babies, are often exposed to broad spectrum antibiotics that alter the gut microbiome. His work shows the requirement of normal gut flora for the education and migration of innate lymphocytes needed to protect the lung from infection. These findings explain the relationship between the widespread use of antibiotics and increased susceptibility of the newborn lung to bacterial infections.