Asthma and allergic disease are major public health problems. The recruitment and activation of eosinophils in the airways play a pivotal role in the pathogenesis of these diseases. Recent studies suggest that CC chemokines such as eotaxin, RANTES, MCP-3, and MCP-4 are important eosinophil chemoattractants. The chemotactic responses of eosinophils is mostly mediated by the CC chemokine receptor-3 (CCR3), which is also expressed on Th2 cells and basophils. CCR3 is a co-receptor for macrophage-tropic human immunodeficiency virus (HIV). The signaling mechanisms of CCR3 is unknown. The goal of this research project is delineate the signal transduction mechanism of CCR3 leading to eosinophil chemotaxis. The hypothesis of the proposal is that the MAP kinase signaling pathway plays a critical role in CCR-3 mediated eosinophil chemotaxis. We postulate that ERK2 and p38 MAP kinases activate myosin light chain kinases, which stimulates myosin II. The ATPase activity of myosin II is critical for generation of energy for locomotion. The p38 MAP kinase is additionally important for cellular adhesion and lamellipod formation.
Specific Aim 1 will examine the activation of ERK, JNK and p38 MAP kinases in eotaxin-stimulated eosinophils and will establish their functional relevance.
Specific Aim 2 will dissect the mechanism by MAP kinases regulated four phases of chemotaxin, i.e. lamellipod formation, adhesion, traction, and de- adhesion.
Specific Aim 3 will investigate the importance of MAP kinases in the activation of myosin light-chain kinase and myosin II. Finally, Specific Aim 4 will address the importance of MAP kinases in airway eosinophil recruitment in vivo. We have previously delineated major signaling pathways of IL-5 using eosinophils. Thus, we have the necessary expertise to perform signaling studies in eosinophils. The research proposal has important basic science and clinical implications. The delineation of the molecular mechanism of eotaxin action will advance basic knowledge. The identification of critical signaling molecules of CCR3 will help design novel therapeutic targets for asthma and allergic diseases. Eosinophil activation is the central theme of the center grant application. The signaling studies of this project will complement and enhance similar components of other projects and is likely to yield synergistic effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI046004-03
Application #
6487738
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2001-09-01
Project End
2002-08-31
Budget Start
Budget End
Support Year
3
Fiscal Year
2001
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Type
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Welliver, Timothy P; Reed, Jennifer L; Welliver Sr, Robert C (2008) Respiratory syncytial virus and influenza virus infections: observations from tissues of fatal infant cases. Pediatr Infect Dis J 27:S92-6
Garofalo, Roberto P; Hintz, Karen H; Hill, Vanessa et al. (2005) A comparison of epidemiologic and immunologic features of bronchiolitis caused by influenza virus and respiratory syncytial virus. J Med Virol 75:282-9
Bacsi, Attila; Dharajiya, Nilesh; Choudhury, Barun K et al. (2005) Effect of pollen-mediated oxidative stress on immediate hypersensitivity reactions and late-phase inflammation in allergic conjunctivitis. J Allergy Clin Immunol 116:836-43
Boldogh, Istvan; Bacsi, Attila; Choudhury, Barun K et al. (2005) ROS generated by pollen NADPH oxidase provide a signal that augments antigen-induced allergic airway inflammation. J Clin Invest 115:2169-79
Garofalo, Roberto P; Hintz, Karen H; Hill, Vanessa et al. (2004) Production of interferon gamma in respiratory syncytial virus infection of humans is not associated with interleukins 12 and 18. J Med Virol 73:289-94
Haeberle, Helene A; Casola, Antonella; Gatalica, Zoran et al. (2004) IkappaB kinase is a critical regulator of chemokine expression and lung inflammation in respiratory syncytial virus infection. J Virol 78:2232-41
Gorska, Magdalena M; Stafford, Susan J; Cen, Osman et al. (2004) Unc119, a novel activator of Lck/Fyn, is essential for T cell activation. J Exp Med 199:369-79
Cen, Osman; Gorska, Magdalena M; Stafford, Susan J et al. (2003) Identification of UNC119 as a novel activator of SRC-type tyrosine kinases. J Biol Chem 278:8837-45
Adachi, Tetsuya; Stafford, Susan; Kayaba, Hiroyuki et al. (2003) Myosin light chain kinase mediates eosinophil chemotaxis in a mitogen-activated protein kinase-dependent manner. J Allergy Clin Immunol 111:113-6
Leonard, Patricia; Sur, Sanjiv (2003) Interleukin-12: potential role in asthma therapy. BioDrugs 17:1-7

Showing the most recent 10 out of 20 publications