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.