Mononuclear phagocytes mediate physiological and pathological processes in the lung. In host defense and in the regulation of the pulmonary environment, there is evolving evidence that these cells participate in the response to lung injury. Our data suggest that mononuclear phagocytes are intimately involved in lung fibrosis. Others agree, as the number of mononuclear phagocytes in the lungs of IFF patients predicts pulmonary function and symptoms. SHIP1 and SHIP2 negatively regulate M-CSF-induced Akt and NF-?B activation and cellular activation and survival. The serine threonine kinase Akt1 is important in cellular survival and differentiation. In this revised proposal we will focus on understanding how SHIP 1/2 regulates monocyte survival and differentiation and Akt1 in M-CSF-stimulated cells. Using macrophages that express constitutively active myristoylated Akt1 (myr-Akt1), we will investigate the role of Akt1 in survival and differentiation of these cells. We will also investigate the molecular mechanism by which bleomycin worsens fibrosis in myr-Akt1 mice. We will also define the role of the src family kinase Lyn in SHIP1 function. We will investigate the role of Akt1 expression in mononuclear phagocytes in vitro and in vivo in this revised proposal and determine the regulation of Akt1 by SHIP1 and SHIP2 in M-CSF-stimulated cells as important regulators of this biochemical pathway and seek to understand the relevance of these events in lung fibrosis and remodeling. To accomplish these goals, we will pursue the following Specific Aims.
Specific Aim 1) To understand the role of Akt1 in the survival and differentiation of mononuclear phagocytes.
Specific Aim 2) To understand the role of SHIP-1 and SHIP-2 in mononuclear phagocyte differentiation and survival.
Specific Aim 3) To understand the molecular mechanisms of bleomycin-induced lung fibrosis and inflammation in mice with macrophage selective myr-Akt1 expression compared to wild type animals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067176-09
Application #
8019534
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Eu, Jerry Pc
Project Start
2001-06-05
Project End
2014-01-31
Budget Start
2011-02-01
Budget End
2014-01-31
Support Year
9
Fiscal Year
2011
Total Cost
$375,000
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Moldovan, Leni; Batte, Kara E; Trgovcich, Joanne et al. (2014) Methodological challenges in utilizing miRNAs as circulating biomarkers. J Cell Mol Med 18:371-90
Voorhees, Jeffrey L; Powell, Nicole D; Moldovan, Leni et al. (2013) Chronic restraint stress upregulates erythropoiesis through glucocorticoid stimulation. PLoS One 8:e77935
Ismail, Noura; Wang, Yijie; Dakhlallah, Duaa et al. (2013) Macrophage microvesicles induce macrophage differentiation and miR-223 transfer. Blood 121:984-95
Voorhees, Jeffrey L; Tarr, Andrew J; Wohleb, Eric S et al. (2013) Prolonged restraint stress increases IL-6, reduces IL-10, and causes persistent depressive-like behavior that is reversed by recombinant IL-10. PLoS One 8:e58488
Dakhlallah, Duaa; Batte, Kara; Wang, Yijie et al. (2013) Epigenetic regulation of miR-17~92 contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 187:397-405
Nuovo, Gerard J; Hagood, James S; Magro, Cynthia M et al. (2012) The distribution of immunomodulatory cells in the lungs of patients with idiopathic pulmonary fibrosis. Mod Pathol 25:416-33
Chen, Duan; Roda, Julie M; Marsh, Clay B et al. (2012) Hypoxia inducible factors-mediated inhibition of cancer by GM-CSF: a mathematical model. Bull Math Biol 74:2752-77
Folcik, Virginia A; Broderick, Gordon; Mohan, Shunmugam et al. (2011) Using an agent-based model to analyze the dynamic communication network of the immune response. Theor Biol Med Model 8:1
Fischer, Sara N; Johnson, Jed K; Baran, Christopher P et al. (2011) Organ-derived coatings on electrospun nanofibers as ex vivo microenvironments. Biomaterials 32:538-46
Wang, Yijie; Mo, Xiaokui; Piper, Melissa G et al. (2011) M-CSF induces monocyte survival by activating NF-*B p65 phosphorylation at Ser276 via protein kinase C. PLoS One 6:e28081

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