Project 1: PCaP-GIS: A Geospatial Analysis of Environmental Risk Factors for Prostate Cancer Severity in North Carolina
Project 2: New Statistical Approaches for Combining Multiple-Source Environmental Data
Project 3: Changes in Toenail Concentration of Trace Elements in Relation to Cardiovascular Disease Risk Factors
Project 4: Mutations in B-Raf Increase UV Genotoxicity in Melanocytes through Attenuation of DNA-damage Induced Cell-cycle Checkpoints
Project: PCaP-GIS: A Geospatial Analysis of Environmental Risk Factors for Prostate Cancer Severity in North Carolina
African Americans are at greater risk of dying of prostate cancer than whites, in part because of racial differences in tumor characteristics that may reflect differences in etiologic mechanisms. Prior studies suggest that pesticide exposures may increase the risk or severity of prostate cancer, and it has been hypothesized that African Americans may be more highly exposed or susceptible to pesticide-mediated carcinogenesis than whites. The PCaP Geographic Information Study (PCaP-GIS) study will be based on existing data from approximately 450 African American and 450 white North Carolina prostate cancer patients enrolled in the North Carolina Louisiana Prostate Cancer Project (PCaP), a population-based study of racial disparities in prostate cancer aggressiveness. Community-level markers of pesticide exposures and healthcare availability will be derived using spatial statistics, and will be analyzed in combination with PCaP interview data concerning race, farming, pesticide-associated occupations and healthcare access to estimate race-specific associations between pesticides and prostate cancer aggressiveness. The PCaP-GIS will provide a unique and cost-efficient opportunity to evaluate environmental factors that may contribute to racial differences in prostate cancer severity among North Carolina men.
Project: New Statistical Approaches for Combining Multiple-Source Environmental Data
We propose to develop statistical methodology that allows researchers to incorporate latent variables, useful in summarizing high-dimensional exposures, and complex spatial correlation structures in one common framework. This work is challenging methodologically due to non-normal measured variables, spatial misalignment, and the need for spatial change of support techniques. In addition, we will incorporate methods for measurement error and uncertainty analysis. We will apply these methods to a study of physical activity in women after pregnancy, exploring whether air pollution levels, meteorological variables, and the built and perceived environment (e.g., conduciveness of neighborhood to physical activity) affect physical activity levels. These methods are widely applicable to other settings, including the National Children’s Study, e.g. in the planned analysis of indoor exposures and environment, air pollution, and childhood asthma incidence and exacerbations. These methods will be applicable when researchers wish to combine spatial methods with hierarchical or random effects models and thus have far-reaching potential applications.
Project: Changes in Toenail Concentration of Trace Elements in Relation to Cardiovascular Disease Risk Factors
The importance of trace elements from both dietary and environmental sources in relation to human health has been increasingly recognized. Some trace elements have nutritional benefits and others can be toxic to human health. Growing evidence suggests that certain trace elements (Hg, Cd, As, Pb, Se, and Cr) may be associated with cardiovascular disease (CVD) risk factors including metabolic syndrome, markers of inflammation, hypertension, and sub-clinical atherosclerosis. However, the longitudinal associations of trace elements in early life with the evolution of CVD risk factors are largely unknown. The overall objective is to examine changes in selected trace element concentrations in toenails in relation to the development of CVD risk factors and sub-clinical atherosclerosis among young adults in the ongoing longitudinal study of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The purposes of this pilot study are: to demonstrate the feasibility of the second toenail collection in a randomly selected sub-cohort of CARDIA; to determine the distributions of changes in selected trace element among gender and ethnic groups; and to generate preliminary data for future grant application.
Project: Mutations in B-Raf Increase UV Genotoxicity in Melanocytes through Attenuation of DNA-damage Induced Cell-cycle Checkpoints
Defects in DNA damage responses may underlie genetic instability and malignant progression in melanoma. Indeed melanomas harboring the most common mutation [B-Raf(V600E)] all exhibit attenuation in their DNA damage induced G2 checkpoint response. The molecular basis and biological result of this correlation between the B-Raf mutation and checkpoint attenuation is not clear. This proposal aims to begin to test the hypothesis that mutations in B-Raf result in attenuation of the DNA damage G2 checkpoint response and that this attenuation results in an increased sensitivity to UV induced mutations in additional genes such as CDKN2A, a gene frequently mutated in melanoma. This hypothesis will be tested by introduction of the B-Raf(V600E) allele into normal human melanocytes followed by precise measurements of the affects on cell cycle, including the DNA damage induced G2 checkpoint response. The majority of time in this proposal will be spent deriving the cell lines with which to test the hypothesis. We anticipate that these cell lines will be useful reagents for further studies of the early stages of melanoma progression regardless of the validity of the hypothesis.
Project: STAT3: An Inhibitory Factor on Obesity-associated Inflammation and Insulin Resistance
Obesity-associated proinflammatory state and insulin resistance play an important role in the development of metabolic syndrome. STAT3 is a transcription factor that mediates the signaling of proinflammatory cytokines, induces cell cycle progression, and prevents apoptosis. This proposal tests the hypothesis that STAT3 in adipose tissue regulates the expression of proinflammatory genes and STAT3 deficiency in this tissue results in the inhibition of proinflammatory state, thus preventing insulin resistance. This hypothesis is based on our preliminary data showing that the ASKO mice are obese, but not diabetic when fed a low-fat diet. The specific aims are to: 1) determine the inflammatory status of low-fat diet fed ASKO mice; 2) determine whether a high-fat diet induces a proinflammatory state and insulin resistance in ASKO mice; and 3) determine what genes are affected in the adipose tissues of high-fat diet fed ASKO mice. This study will generate important pilot data for a future R01 proposal. It will help to understand the interaction between obesogenic environmental factors and developmental determinants of obesity and metabolic syndrome and to inform studies of new therapeutic approaches.
|Funded by NIEHS Grant # P30 ES010126|