This Cancer Prevention, Control and Population Sciences Career Development Award is being requested to support the further development of Dr. Nora L. Nock into an independent investigator focusing on pathway modeling of energy balance and toxin response systems to help define exercise and diet interventions that will improve cancer control and prevention. Toxins such as polycyclic aromatic hydrocarbons (PAHs), which are ubiquitous and can create direct (PAH-DNA adduct) and indirect oxidative (8-oxo-dG) DNA damage, and genetic polymorphisms in their metabolism, conjugation and DNA repair have been equivocally associated with several cancers including prostate and colon. Physical activity (PA), a component of energy balance, has been consistently associated with colon cancer but reports in other cancers are inconsistent. Moreover, because exercise of sufficient intensity can upregulate antioxidant and other toxin defense mechanisms and lipophilic toxins (PAHs) can bioaccumulate in body fat, physical activity and other components of energy balance may modify effects of toxin exposure. To advance our knowledge of the role these systems play in carcinogenesis, biological systems-based modeling methods that incorporate genotype, phenotype (gene expression) and other epidemiological data are needed. Dr. Nock has been trained in genetic epidemiology but requires additional mentored training in statistical frameworks that solve systems of linear and non-linear equations including structural equation modeling (SEM) and physiologically-based toxico-kinetic/dynamic (PBTK/TD) modeling to undertake this pathway modeling. Dr. Nock would also benefit from explicit training in nutritional and exercise sciences. The proposed training program includes mentored research, graduate coursework and presentations at relevant national meetings. In the research plan, Dr. Nock proposes to integrate genotype-phenotype and biomarker measures into SEM and PBTK/TD statistical frameworks;and, apply these methods to modeling energy balance and toxin response systems using data from two cancer studies. The prostate cancer case-control study is unique because it includes biomarkers of effective PAH dose, candidate genes in PAH metabolism, conjugation and DNA repair and energy balance measures. The colon polyps case-control study is part of the Transdisciplinary Research on Energetics and Cancer program and enables evaluation of biomarkers and candidate genes in energy balance and toxin response systems.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic/Teacher Award (ATA) (K07)
Project #
5K07CA129162-05
Application #
8299413
Study Section
Subcommittee G - Education (NCI)
Program Officer
Perkins, Susan N
Project Start
2008-08-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$129,442
Indirect Cost
$9,588
Name
Case Western Reserve University
Department
Genetics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Stein, Catherine M; Morris, Nathan J; Nock, Nora L (2012) Structural equation modeling. Methods Mol Biol 850:495-512
Tintle, Nathan; Aschard, Hugues; Hu, Inchi et al. (2011) Inflated type I error rates when using aggregation methods to analyze rare variants in the 1000 Genomes Project exon sequencing data in unrelated individuals: summary results from Group 7 at Genetic Analysis Workshop 17. Genet Epidemiol 35 Suppl 1:S56-60
Nock, Nora L; Plummer, Sarah J; Thompson, Cheryl L et al. (2011) FTO polymorphisms are associated with adult body mass index (BMI) and colorectal adenomas in African-Americans. Carcinogenesis 32:748-56
Nock, Nora L; Patrick-Melin, Aimee; Cook, Marc et al. (2011) Higher bone mineral density is associated with a decreased risk of colorectal adenomas. Int J Cancer 129:956-64
Nock, Nora; Bock, Cathryn; Neslund-Dudas, Christine et al. (2009) Polymorphisms in glutathione S-transferase genes increase risk of prostate cancer biochemical recurrence differentially by ethnicity and disease severity. Cancer Causes Control :
Nock, Nora L; Li, Li; Larkin, Emma K et al. (2009) Empirical evidence for "syndrome Z": a hierarchical 5-factor model of the metabolic syndrome incorporating sleep disturbance measures. Sleep 32:615-22