Research

In newborns and young children at risk of disease, comprehensive measurement of developmental programs and environmental response requires both cutting edge assay technologies and novel informatics approaches. We have been consistently early adopters of innovative platforms with emphasis on understanding longitudinal changes in gene expression and functional differences between individuals. Our successes have largely relied on outstanding collaborations between physicians, biologists, and computer scientists.

Sahoo D, Zaramela LS, Hernandez GE, Mai U, Taheri S, Dang D, Stouch AN, Medal RM, McCoy AM, Aschner JL, Blackwell TS, Zengler K, Prince LS. Transcriptional profiling of lung macrophages identifies a predictive signature for inflammatory lung disease in preterm infants. Commun Biol. 2020 May 22;3(1):259. PMC7244484.

Dang D, Taheri S, Das S, Ghosh P, Prince LS, Sahoo D. Computational Approach to Identifying Universal Macrophage Biomarkers. Front Physiol. 2020;11:275. PMC7156600.

Kingsmore SF, Cakici JA, Clark MM, Gaughran M, Feddock M, Batalov S, Bainbridge MN, Carroll J, Caylor SA, Clarke C, Ding Y, Ellsworth K, Farnaes L, Hildreth A, Hobbs C, James K, Kint CI, Lenberg J, Nahas S, Prince L, Reyes I, Salz L, Sanford E, Schols P, Sweeney N, Tokita M, Veeraraghavan N, Watkins K, Wigby K, Wong T, Chowdhury S, Wright MS, Dimmock D. A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants. Am J Hum Genet. 2019 Oct 3;105(4):719-733. PMC6817534.

Medal RM, Im AM, Yamamoto Y, Lakhdari O, Blackwell TS, Hoffman HM, Sahoo D, Prince LS. The innate immune response in fetal lung mesenchymal cells targets VEGFR2 expression and activity. Am J Physiol Lung Cell Mol Physiol. 2017 Jun 1;312(6):L861-L872. PMC5495951.

As we have learned more about the mechanisms of neonatal lung injury, our lab has focused more on the unique developmental paradigms related to the lung innate immune system. We were the first to show that macrophages within developing fetal lung tissue could be functionally activated to release inflammatory mediators and inhibit lung morphogenesis. Interestingly, activating fetal lung macrophages drives their differentiation along a unique cell lineage path that does not correspond to previously proposed M1/M2 macrophage subtypes. More recent work established the key roles of IL-1beta and the NLRP3 inflammasome in linking macrophage activation to lung injury and abnormal lung morphogenesis. Inflammasome expression and function increase throughout embryonic development, establishing windows of time during which the fetal and newborn lung acquires the ability to mount a robust immune response. Current projects are focused on how immune activation affects macrophage development at the transcriptional level, the unique properties of different macrophage populations in the embryonic and newborn lung, and the molecular and cellular mechanisms responsible for the neonatal susceptibility to lung infection. Our data consistently discover new insight and challenge existing paradigms related to the development of neonatal immunity.

Honda A, Hoeksema MA, Sakai M, Lund SJ, Lakhdari O, Butcher LD, Rambaldo TC, Sekiya NM, Nasamran CA, Fisch KM, Sajti E, Glass CK, Prince LS. The Lung Microenvironment Instructs Gene Transcription in Neonatal and Adult Alveolar Macrophages. J Immunol. 2022 Apr 15;208(8):1947-1959. PMID: 35354612

Lund SJ, Patras KA, Kimmey JM, Yamamura A, Butcher LD, Del Rosario PGB, Hernandez GE, McCoy AM, Lakhdari O, Nizet V, Prince LS. Developmental Immaturity of Siglec Receptor Expression on Neonatal Alveolar Macrophages Predisposes to Severe Group B Streptococcal Infection. iScience. 2020 Jun 26;23(6):101207. PMC7300150.

Sajti E, Link VM, Ouyang Z, Spann NJ, Westin E, Romanoski CE, Fonseca GJ, Prince LS, Glass CK. Transcriptomic and epigenetic mechanisms underlying myeloid diversity in the lung. Nat Immunol. 2020 Feb;21(2):221-231. PMC7667722.

Lakhdari O, Yamamura A, Hernandez GE, Anderson KK, Lund SJ, Oppong-Nonterah GO, Hoffman HM, Prince LS. Differential Immune Activation in Fetal Macrophage Populations. Sci Rep. 2019 May 22;9(1):7677. PMC6531440.

Stouch AN, McCoy AM, Greer RM, Lakhdari O, Yull FE, Blackwell TS, Hoffman HM, Prince LS. IL-1β and Inflammasome Activity Link Inflammation to Abnormal Fetal Airway Development. J Immunol. 2016 Apr 15;196(8):3411-20. PMC5315059.

Inflammation disrupts lung development, leading to bronchopulmonary dysplasia (BPD). We have used this clinical observation to unlock potential disease mechanisms. Our lab was the first group to demonstrate that inflammation and NF-kappaB activation specifically disrupted normal expression of molecular targets critical for normal lung morphogenesis and cell differentiation. Ongoing projects are focusing on how inflammatory signals disrupt developmental pathways at a molecular and cellular level.

McCoy AM, Herington JL, Stouch AN, Mukherjee AB, Lakhdari O, Blackwell TS, Prince LS. IKKβ Activation in the Fetal Lung Mesenchyme Alters Lung Vascular Development but Not Airway Morphogenesis. Am J Pathol. 2017 Dec;187(12):2635-2644. PMC5718091.

Medal RM, Im AM, Yamamoto Y, Lakhdari O, Blackwell TS, Hoffman HM, Sahoo D, Prince LS. The innate immune response in fetal lung mesenchymal cells targets VEGFR2 expression and activity. Am J Physiol Lung Cell Mol Physiol. 2017 Jun 1;312(6):L861-L872. PMC5495951.

Stouch AN, McCoy AM, Greer RM, Lakhdari O, Yull FE, Blackwell TS, Hoffman HM, Prince LS. IL-1β and Inflammasome Activity Link Inflammation to Abnormal Fetal Airway Development. J Immunol. 2016 Apr 15;196(8):3411-20. PMC5315059.

Carver BJ, Plosa EJ, Stinnett AM, Blackwell TS, Prince LS. Interactions between NF-κB and SP3 connect inflammatory signaling with reduced FGF-10 expression. J Biol Chem. 2013 May 24;288(21):15318-25. PMC3663551.

Benjamin JT, Gaston DC, Halloran BA, Schnapp LM, Zent R, Prince LS. The role of integrin alpha8beta1 in fetal lung morphogenesis and injury. Dev Biol. 2009 Nov 15;335(2):407-17. PMID: 19769957