This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.It is well documented that inherited genetic traits play a critical role in individual susceptibility to tobacco-related cancers. Recently, several sequence variations (polymorphisms) coding for amino acid changes in DNA repair genes have been identified; however, little is known about their effects on cellular responses to genetic damage induced by exposure to tobacco smoke. We will investigate the roles of polymorphisms in several DNA repair genes (e.g. XRCC1, XRCC3, and XPD) involved in three major DNA repair pathways), while taking into consideration the role of influential polymorphisms in genes for biotransformation enzymes. We hypothesize that inherited polymorphisms coding for amino acid changes in DNA repair genes affect the efficiency of DNA repair, thus leading to increased accumulation of genetic damage in response to smoking at both the chromosomal and gene levels. We will test our hypothesis in a population of 400 non-symptomatic smokers and 400 healthy non-smokers. We will use biomarkers of exposure (cotinine levels in plasma) and of biological effects (cytogenetic end points and somatic cell gene mutations) to investigate the influence of DNA repair polymorphisms on the induction of genetic damage. In addition, in controlled in vitro experiments, we will determine the roles of these polymorphisms in the induction of genetic damage in cultured cells exposed to model tobacco carcinogens. The study will also have significant implications for understanding the role of these polymorphisms in smoking-associated cancer risk. Knowledge gained from the study is critical for providing new mechanistic explanations for differential susceptibility to tobacco smoking.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
General Clinical Research Centers Program (M01)
Project #
5M01RR000073-45
Application #
7719174
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
2008-04-01
Project End
2009-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
45
Fiscal Year
2008
Total Cost
$19,211
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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