Development of laboratory procedures for handling a variety of sample types. Establishment of the NIH Bioinformatics Cooperative (http://affylims.cit.nih.gov/); development and dissemination of the MSCL toolbox; construction of a database containing over 4000 microarrays. Co-founded the NIH sponsored Symposium on the Functional Genomics of Critical Illness and Injury. The seven meetings in this series (last: December 2009) focused on knowledge emerging from functional genomic databases relevant to critical care medicine. This meeting led to the formation of the US Critical Illness and Injury Trials Group (USCIITG: www.usciitg.org/), as a forum to further investigator initiated Intensive Care Medicine research on a national scale. Interactions between IFN-alpha and dexamethasone were investigated in primary bronchial epithelial cells (Physiologic Genomics 2005). Dexamethasone was found to broadly suppress late IFN-alpha-induced responses. Global transcriptional analysis of circulating leukocytes highlighted the intense oxidant and inflammatory nature of steady-state sickle cell disease and provided insight into broad compensatory responses to vascular injury (Blood 2004). The human reticulocyte transcriptome was characterized further extending our understanding of circulating cell-types (Physiol Genomics 2007). Expression profiling of platelets in sickle cell disease associate circulatory stress in this disorder with abnormalities of arginine metabolism (Circulation 2007). Single dose intravenous endotoxin administration to humans produced a rich profile of gene expression changes in blood (Physiol Genomics 2006). Induced genes included pattern recognition molecules, intracellular signaling and transcription, cell mobility, and defense function. T lymphocyte-associated genes were repressed. Notably, these alterations in gene expression were rapidly extinguished within 24 h. Gene expression profiling was used to globally identify numerous genes regulated by NO. This work led to the discovery of new signal transduction pathways and regulatory mechanisms by which NO influences inflammation and cell proliferation (BMC Genomics 2005; Nuc Acid Res 2006; J Biol Chem 2006). A germline activating mutation in NRAS was discovered as the underlying cause of an undifferentiated case of human autoimmune lymphoproliferative syndrome (PNAS 2007). This finding suggested that RAS-inactivating drugs, such as farnesyltransferase inhibitors might be therapeutically useful in human autoimmune disorders. The innate and adaptive immune response to Pneumocystis was characterized in wild type and CD40-ligand knockout mice (J Leukoc Biol 2008). In the field of metabolic diseases, a focused mitochondria/metabolism/inflammation microarray was used to study HIV-associated myopathy/fatigue (Biol Res Nurs 2008; J Infect Dis 2012; Biol Res Nurs 2013). Genome-wide microarrays uncovered the importance of leptin and the thermogenic glycerolipid/fatty acid cycling pathway in protecting the heart from diet-induced steatosis (Physiological Genomics 2011). Microarrays were also used to globally examine the ability of carbon monoxide, an endogenous messenger produced by heme oxygenase, to suppress LPS-mediated gene induction in human monocytes (PLoS One 2009). Other studies examined the transcriptome of endothelial progenitor cells (Arteriosclerosis Thrombosis and Vascular Biology 2009), animal strain effects on PBMC gene expression in a rat model of acute cardiac rejection (BMC Genomics 2009), and differences between CD4+ and CD8+ effector T cells in antitumor immunity (PNAS 2009). Targeted studies of specific inflammatory responses investigated gene regulation mediated by leukotriene D(4) activation of the type I cysteinyl leukotriene receptor (J Allergy Clin Immunol 2008) and the redundancy of leukotriene B(4) and D(4) signaling (Allergy 2011) in human monocytes. In air-liquid interface differentiated normal human bronchial epithelial cells challenged with IFNγ, O2 (70%) and NO (40 ppm), two gases used in the management of ARDS, produced highly similar signatures of oxidant stress, possibly explaining the lack of benefit from NO despite its ability to lower O2 requirements (American Thoracic Society abstract 2011). Specific miRNAs in human airway epithelial cells were found to control gene and protein expression important for differentiation (Am J Respir Cell Mol Biol 2013). Dendritic cells (DCs) comprise distinct populations with specialized immune-regulatory functions. Retinoic acid (RA), a vitamin A derivative, was found to control the homeostasis of dendritic cell (DC) precursors. Total body radiation in patients and mice led to a selective loss of RA-dependent DC subsets and impaired class IIrestricted auto and antitumor immunity that could be rescued by supplemental RA (J Exp Med 2013). Global gene-expression changes across multiple organs implicated a host-wide IFN-response in staphylococcal enterotoxin B (SEB)-induced death. Therapies aimed at IFN-associated innate immunity may improve outcome in toxic shock syndromes (PLoS One 2014). After cord blood/haploidentical transplantation, engraftment of donor cells with germ-line integration of HHV6 mimics HHV6 reactivation (Blood 2014). Circulating endothelial cells (CECs) have been proposed as a biomarker of vascular injury. CECs were identified by flow cytometry and their endothelial phenotype was validated using ultramicro analytical immunochemistry. Most CECs in healthy individuals are senescent without an identifiable nucleus and lacking sufficient RNA for transcriptomal analysis (Thrombosis and Haemostasis 2014). Mutations in the BMPR2 gene leading to loss-of-function are the most common cause of heritable PAH. Global expression profiling in BMPR2-silenced human pulmonary artery endothelial cells (PAECs) linked oncogenic Ras/Raf/ERK signaling to phenotypic changes including proliferation, invasiveness and cytoskeletal abnormalities. The Ras/Raf/ERK pathway was found to be activated in these cells. Treatment with Raf inhibitors and nintedanib, an inhibitor of receptor tyrosine kinases upstream from Ras, corrected some of the phenotypic alterations associated with BMPR2 silencing. Therapeutics targeting non-canonical Raf/ERK signaling may be useful in preventing or reversing vascular remodeling in patients with PAH (J Am College Cardiol abstract 2014; manuscript submitted 2015). In human endothelial cells, MR agonists were found to repress NF-κB mediated gene transcription (Keystone Symposia on Nuclear Receptors abstract 2010; American Thoracic Society abstract 2010). In contrast, MR either repressed or further activated AP1 signaling depending on the DNA sequence of specific AP1 binding sites, MR ligand structure, and AP1 family member expression. Global expression profiling identified target genes that were trans-activated by this MR/AP1-dependent pro-inflammatory mechanism (In preparation 2015).

Agency
National Institute of Health (NIH)
Institute
Clinical Center (CLC)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIACL001164-16
Application #
9154047
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Clinical Center
Department
Type
DUNS #
City
State
Country
Zip Code
Tropea, Margaret M; Harper, Bonnie J A; Graninger, Grace M et al. (2014) Isolation of a circulating CD45-, CD34dim cell population and validation of their endothelial phenotype. Thromb Haemost 112:770-80
Purev, Enkhtsetseg; Winkler, Thomas; Danner, Robert L et al. (2014) Engraftment of donor cells with germ-line integration of HHV6 mimics HHV6 reactivation following cord blood/haplo transplantation. Blood 124:1198-9
Ferreyra, Gabriela A; Elinoff, Jason M; Demirkale, Cumhur Y et al. (2014) Late multiple organ surge in interferon-regulated target genes characterizes staphylococcal enterotoxin B lethality. PLoS One 9:e88756
Klebanoff, Christopher A; Spencer, Sean P; Torabi-Parizi, Parizad et al. (2013) Retinoic acid controls the homeostasis of pre-cDC-derived splenic and intestinal dendritic cells. J Exp Med 210:1961-76
Martinez-Anton, Asuncion; Sokolowska, Milena; Kern, Steven et al. (2013) Changes in microRNA and mRNA expression with differentiation of human bronchial epithelial cells. Am J Respir Cell Mol Biol 49:384-95
Voss, Joachim G; Dobra, Adrian; Morse, Caryn et al. (2013) Fatigue-related gene networks identified in CD14+ cells isolated from HIV-infected patients: part II: statistical analysis. Biol Res Nurs 15:152-9
Voss, Joachim G; Dobra, Adrian; Morse, Caryn et al. (2013) Fatigue-related gene networks identified in CD(14)+ cells isolated from HIV-infected patients: part I: research findings. Biol Res Nurs 15:137-51
Morse, Caryn G; Voss, Joachim G; Rakocevic, Goran et al. (2012) HIV infection and antiretroviral therapy have divergent effects on mitochondria in adipose tissue. J Infect Dis 205:1778-87
Muranski, Pawel; Borman, Zachary A; Kerkar, Sid P et al. (2011) Th17 cells are long lived and retain a stem cell-like molecular signature. Immunity 35:972-85
Rame, J Eduardo; Barouch, Lili A; Sack, Michael N et al. (2011) Caloric restriction in leptin deficiency does not correct myocardial steatosis: failure to normalize PPAR{alpha}/PGC1{alpha} and thermogenic glycerolipid/fatty acid cycling. Physiol Genomics 43:726-38

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