Asthma is considered a chronic inflammatory disease. It involves complex interactions between exogenous [environmental] and endogenous [genetic] factors. The long-term objective of this research is to understand the molecular mechanisms by which environmental exposures can influence the development of asthma. CD 14 is the main receptor for LPS and other bacterial """"""""danger"""""""" signals. Our group has found five polymorphisms in the promoter region of the CD14 gene (positions -159, -809, -1145, -1359, -1619 from the transcription start site). We hypothesize that polymorphisms in the promoter region of the CD 14 gene may alter expression of CD 14, and this in turn could alter an individuals sensitivity to LPS exposure. This proposal is for career development in the area of Molecular Epidemiology, which is designed to integrate Epidemiology and Molecular Biology through research and didactic training.
The research aims of this project are (1) to determine the association between an acute response to LPS inhalation and genetic polymorphisms in the CD 14 gene; (2) to elucidate the specific role of the CD 14 polymorphisms in CD 14 gene transcription in the context of a population; and (3) to associate an individual's CD 14 transcriptional activity with serum CD 14 and membrane CD 14 accumulation as a function of CD 14 promoter genotypes and putative haplotypes. The didactic goals of this grant are (1) to complete a Masters degree in Epidemiology; (2) to develop and teach a 16-week course on Molecular Epidemiology; (3) to join the International Molecular Epidemiology Task Force; and (4) to attend conferences/short courses on Molecular Epidemiology, Genetic Epidemiology, Occupational Exposures and/or Respiratory Disease. Completion of these research and, didactic goals will allow the candidate to become an independent researcher in the field of Molecular Epidemiology, with particular emphasis on the study of the molecular biology of genes that influence respiratory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01ES000386-04
Application #
6687303
Study Section
Special Emphasis Panel (ZES1-LKB-C (K1))
Program Officer
Shreffler, Carol K
Project Start
2001-01-29
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
4
Fiscal Year
2004
Total Cost
$99,716
Indirect Cost
Name
University of Arizona
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Levan, Tricia D; Michel, Olivier; Dentener, Mieke et al. (2008) Association between CD14 polymorphisms and serum soluble CD14 levels: effect of atopy and endotoxin inhalation. J Allergy Clin Immunol 121:434-440.e1
LeVan, T D; Guerra, S; Klimecki, W et al. (2006) The impact of CD14 polymorphisms on the development of soluble CD14 levels during infancy. Genes Immun 7:77-80
LeVan, Tricia D; Koh, Woon-Puay; Lee, Hin-Peng et al. (2006) Vapor, dust, and smoke exposure in relation to adult-onset asthma and chronic respiratory symptoms: the Singapore Chinese Health Study. Am J Epidemiol 163:1118-28
Michel, Olivier; LeVan, Tricia D; Stern, Debbie et al. (2003) Systemic responsiveness to lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings. J Allergy Clin Immunol 112:923-9
LeVan, T D; Bloom, J W; Bailey, T J et al. (2001) A common single nucleotide polymorphism in the CD14 promoter decreases the affinity of Sp protein binding and enhances transcriptional activity. J Immunol 167:5838-44