The guiding hypothesis of this SCOR renewal is that allergic asthma results from a dysregulated immune response to allergens. The dysregulated immune response sets in motion a cascade resulting in the accumulation of IgE-sensitized mast cells and allergen-specific Th2 cells in airway mucosa, airway hyperreactivity, eosinophilic inflammation and airway remodeling with mucous cell metaplasia. The proposal consists of four projects, each with a clinical component, and three supporting cores, including a clinical core. Dr. Lipscomb's project proposes to study the role of lung antigen presenting cells, particularly lung dendritic cells (DCs), in pulmonary immune responses to allergens. Lipscomb will adoptively transfer T cell clones and lung DCs in a murine allergic pulmonary inflammation model and use human monocyte-derived DCs, human bronchoalveolar lavage fluids and bronchial biopsies in these studies. Dr. Oliver's project will exploit her laboratory's observation showing that basophils that don't release histamine following high affinity IgE receptor (FceRI) crossing-linking are deficient in the tyrosine kinase, Syk. Oliver proposes to determine whether people with such """"""""non-releaser"""""""" basophils are protected from asthma. She will also explore the mechanisms for loss of Syk activity in non-releaser basophils and assess whether decreased serum IgE induced by anti-IgE therapy leads to a decrease in FceRI expression on human lung mast cells. Dr. Sklar's project will examine the molecular mechanisms involved in the preferential recruitment of eosinophils and basophils into the bronchial mucosa in asthma. Sklar will use novel technology to quantify changes in affinity and avidity of the molecules involved in the cell-cell interactions that model leukocyte adhesion to the endothelium. Dr. Tesfaigzi's project proposes to study the role of mediators generated in asthmatic lungs in causing mucous cell metaplasia. Specifically, Tesfaigzi win seek a role for suppression of normal apoptosis by the pro-apoptotic regulator, Bax, in mucous cell metaplasia. He will use an innovative mouse bronchiolar explant model, cytokine receptor and Bax knockout mice, human bronchial brushings, and autopsy tissues from asthmatics and controls. Collectively, the four projects will identify mechanisms involved in critical pathways that lead to asthmatic lung inflammation and bronchial remodeling with the goal of identifying possible targets for prevention or treatment of asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL056384-08
Application #
6685190
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M1))
Program Officer
Banks-Schlegel, Susan P
Project Start
1996-12-01
Project End
2006-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
8
Fiscal Year
2004
Total Cost
$1,488,464
Indirect Cost
Name
University of New Mexico
Department
Pathology
Type
Schools of Medicine
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Chand, Hitendra S; Montano, Gilbert; Huang, Xuesong et al. (2014) A genetic variant of p53 restricts the mucous secretory phenotype by regulating SPDEF and Bcl-2 expression. Nat Commun 5:5567
Chand, Hitendra S; Schuyler, Mark; Joste, Nancy et al. (2010) Anti-IgE therapy results in decreased myeloid dendritic cells in asthmatic airways. J Allergy Clin Immunol 125:1157-1158.e5
Oliver, Janet M; Tarleton, Christy A; Gilmartin, Laura et al. (2010) Reduced FcepsilonRI-mediated release of asthma-promoting cytokines and chemokines from human basophils during omalizumab therapy. Int Arch Allergy Immunol 151:275-84
Chigaev, Alexandre; Waller, Anna; Amit, Or et al. (2009) Real-time analysis of conformation-sensitive antibody binding provides new insights into integrin conformational regulation. J Biol Chem 284:14337-46
Hahn, Andrew C; Lyons, C Rick; Lipscomb, Mary F (2008) Effect of Bacillus anthracis virulence factors on human dendritic cell activation. Hum Immunol 69:552-61
Chigaev, Alexandre; Waller, Anna; Amit, Or et al. (2008) Galphas-coupled receptor signaling actively down-regulates alpha4beta1-integrin affinity: a possible mechanism for cell de-adhesion. BMC Immunol 9:26
Gilmartin, Laura; Tarleton, Christy A; Schuyler, Mark et al. (2008) A comparison of inflammatory mediators released by basophils of asthmatic and control subjects in response to high-affinity IgE receptor aggregation. Int Arch Allergy Immunol 145:182-92
Chigaev, Alexandre; Waller, Anna; Zwartz, Gordon J et al. (2007) Regulation of cell adhesion by affinity and conformational unbending of alpha4beta1 integrin. J Immunol 178:6828-39
Hernandez-Hansen, Valerie; Bard, Julie D J; Tarleton, Christy A et al. (2005) Increased expression of genes linked to FcepsilonRI Signaling and to cytokine and chemokine production in Lyn-deficient mast cells. J Immunol 175:7880-8
Larson, Richard S; Davis, Terry; Bologa, Cristian et al. (2005) Dissociation of I domain and global conformational changes in LFA-1: refinement of small molecule-I domain structure-activity relationships. Biochemistry 44:4322-31

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