IMPH Research in Nutrition and Physical Activity

Biomarkers of Obesity, Prostate Tissue Inflammation, and BPH Progression 
Cost-Effectiveness of Nutrition Intervention in Long Term Care 
Cost-Effectiveness of Weight Loss Prevention in Nursing Homes: A Controlled Trial 
Exercise and Fuel Metabolism 
Fatty Acid Desaturase Activity, Fish Oil and Colorectal Cancer Chemoprevention 
Genetic and Endocrine Pathways Linking Obesity to Prostate Cancer 
Growing Right Onto Wellness (GROW): Changing Early Childhood BMI Trajectories 
Long-Chain Fatty Acids, Oxidative Stress and Colorectal Neoplasm Risk 
O'Brien Center Development: BPH and Obesity 
Personalized Prevention of Colorectal Cancer 
Pregnancy Folate Status & Early Childhood Respiratory & Atopic Disease Outcomes 
Prevention of Weight Loss in Long Term Care Veterans 
Shanghai Breast Cancer Study (SBCS) 
Shanghai Endometrial Cancer Study (SECS) 
Shanghai Men's Health Study 
Tailoring Healthy Eating and Physical Activity for African American Men

Biomarkers of Obesity, Prostate Tissue Inflammation, and BPH Progression

The purpose of the study is to investigate the relationship between obesity and BPH.  Obesity generates a state of chronic systemic inflammation known to enhance arthrosclerosis, diabetes, and other inflammatory diseases. Several studies also suggest that obese men are also more likely to develop lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH).  However, much of the epidemiologic evidence relies on self-reported BPH outcomes, and there are few, if any, animal models to characterize the obesity-BPH relationship. Thus, our long-term goals are to characterize the relationship between obesity and prostate tissue inflammation and hyperplasia, investigate potential mechanisms by which obesity advances BPH, develop a mouse model of BPH for mechanistic studies, and to conduct a prospective epidemiologic study to investigate the clinical impact of obesity on BPH progression. Read more.

Funding Source: NIH/NIDDK
PI: Jay Fowke

Cost-Effectiveness of Nutrition Intervention in Long Term Care

This funded translational study utilizes the federal regulation to train non-nursing staff for nutritional care delivery.  Specifically, this study uses a controlled, intervention design to determine the cost-effectiveness of a between-meal snack intervention relative to a usual care control group in a group of 200 residents in 4 community nursing homes. Non-nursing staff trained as “feeding assistants” will offer residents in the intervention group a choice between supplements and other snack foods and fluids twice daily, five days per week, for 24 weeks while also providing a standardized prompting protocol to enhance intake and independence in eating.  The impact of the training program on residents’ nutritional status is monitored by research staff during this time period. Read more.

Funding Source: NIH/NIA
PI: Sandra F. Simmons, PhD

Cost-Effectiveness of Weight Loss Prevention in Nursing Homes: A Controlled Trial

This funded study uses a controlled, intervention design to determine the cost-effectiveness of oral liquid nutritional supplements with an alternative nutrition intervention that offers residents a choice between supplements and other foods and fluids (i.e., snacks) between meals in a group of 200 residents in four community nursing homes.  Each intervention is being implemented for 24 weeks while research staff monitor nutritional intake, body weight and other health outcomes. Read more.

Funding Source: Agency for Healthcare Research and Quality
PI:Sandra F. Simmons, PhD

Exercise and Fuel Metabolism

Understanding the pathogenesis of the metabolic syndrome is paramount to eliminating it. Hepatic metabolic dysfunction associated with inadequate substrate oxidation, lipid accumulation, and dyslipidemia is a hallmark of metabolic syndrome as it is evident early in its development and is associated with the severity of other symptoms. It has been speculated that liver metabolic dysfunction is a causative step in the natural progression to metabolic syndrome. Despite the central role of liver metabolism to overall "metabolic health," the mechanism for its effectiveness in healthy physically active states, the factors responsible for dysfunction, and the means to correct dysfunction are poorly understood. The protocols that comprise the extended funding period focus on three Specific Aims that are a continuation of innovative work conducted in the current funding cycle. The Speciic Aims will test in lean and high fat fed mice whether (a) the activation of hepatic energy sensors (AMPK, sirtuins, hypoxia inducible factors) are protective against insulin resistance; (b) the extracellular matrix conveys a spatial barrier or signaling event that contributes to the impaired energetics and nutrient fluxes of insulin resistance; and (c) the hepatic adaptations to high fat feeding and physical activity are AMPK-dependent. The regulation of hepatic metabolism will be studied using surgical, experimental, and isotopic tools that allow well controlled studies to be conducted in the unstressed conscious mouse. Highly innovative approaches will allow the Aims to be addressed with unprecedented resolution of a spectrum of pathophysiological events. We have developed a new, highly innovative, and comprehensive method for measurement of nutrient fluxes in the liver using stable isotopes of glucose, water, and proprionate. Hepatic ECM will be characterized by using a novel proteomic method designed to focus on the ECM, immunohistochemistry, polysaccharide binding protein, and transmission electron microscopy. The ongoing and planned studies provide mechanisms by which environmental factors (diet and exercise) interact with genes to cause or rescue hepatic metabolic dysregulation. The results of these studies will introduce new avenues to our understanding and treatment of metabolic diseases. RELEVANCE (See instructions): The metabolic syndrome is an epidemic in Western Culture. Hepatic metabolic dysfunction associated with lipid accumulation and dyslipidemia is evident early in its development and is associated with the severity of other symptoms. It has been speculated that liver metabolic dysfunction is a causative step in progression to metabolic syndrome. These studies will define how liver metabolism is regulated in the healthy liver and wherfi .<^itfis of dvsfunction lie in the nathonfinesi.q of metabolic syndrome, insulin resistance, and diabetes. Read more.

Funding Source: NIH/NIDDK
PI: David Wasserman

Fatty Acid Desaturase Activity, Fish Oil and Colorectal Cancer Chemoprevention

Observational studies have suggested that the n-3 polyunsaturated fatty acids, eicosapentanoic acid and docosahexanoic acid, may reduce the risk of colorectal cancer. Our hypothesis is that individuals with lower activity of fatty acid desaturase-1(FADS1) will derive greater benefit from fish oil supplementation than individuals with higher FADS1 activity due to lower production of endogenous arachidonic acid. To test this hypothesis we will recruit 150 participants and conduct a 6-month double blind 3 X 2 factorial randomized controlled trial. Our first factor will be FADS1 genotype (GG, GT, and TT) and our second factor will be fish oil supplementation (fish oil versus placebo). Our specific aims include: 1) to determine the efficacy of fish oil supplements on rectal epithelial cell proliferation indexes and markers of rectal crypt apoptosis, and 2) to determine the effect of genetically-determined fatty acid desaturase 1 activity on fish oil supplementation for colorectal cancer chemoprevention. Read more.

Funding Source: NIH/NCI 
PI: Harvey Murff

Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer

The purpose of this study is to investigate the associations between obesity, prostate cancer, and high-grade prostatic intraepithelial neoplasia (PIN). Toward this goal, we developed a multi-centered rapid-recruitment protocol targeting men seeking a diagnostic prostate biopsy within any urology clinic in metro Nashville, TN.  Trained staff measure body size and body composition using bioelectric impedance analysis, collect pre-diagnosis blood and urine for biomarker and genetic analyses, administer a research lifestyle questionnaire, and perform medical chart review for clinical and pathology data.  Genetic and molecular markers of obesity are investigated toward prostate cancer and PIN risk. Read more.

Funding Source: NIH/NCI 
PI: Jay Fowke

Growing Right Onto Wellness (GROW): Changing Early Childhood BMI Trajectories

Food preferences and activity habits set in early childhood can profoundly influence lifelong trajectories for Body l\/lass Index (BMI) and health. Specifically, rapid BMI gain in early childhood has been established to affect adulthood mortality and morbidity. Unfortunately, the longer such unhealthy patterns are in place, the more difficult it can be to reverse them. Therefore, healthy lifestyle interventions targeted at children as early as preschool 'have enormous potential to affect lifelong health. Furthermore, nutrition and activity patterns are determined not only at the child level, but within the family and the community. Building on the success of an existing partnership between Vanderbilt Pediatrics and Metro Parks and Recreation in Nashville, TN, we will conduct and evaluate an intervention intended to prevent obesity in preschoolers in an approach that affects multiple levels of risk and is both family-based and community centered. Prior to launching a large randomized controlled trial (RCT), formative research (focus groups and pilot studies) will be conducted to refine the intervention components. In the RCT, 600 parent-preschool children dyads from low income neighborhoods will be randomly assigned to one of two conditions. In the intervention condition, groups of parent-child dyads will participate in an empirically tested, literacy-sensitive, skills building curriculum to improve: 1) caloric intake with appropriate macronutrients, and 2) routine physical activity for both parent and child. The intervention condition will occur in community centers and utilize tools including goal setting, self-monitoring, and problem solving. In the control condition parent-child dyad groups will receive a literacy promotion/school success curriculum. Both conditions will have 90-minute sessions in: 1) an initiation phase (weekly for 3 months); 2) a maintenance phase (biweekly for 6 months); and 3) a sustainability phase (monthly for 27 months). The primary outcome of interest will be early childhood BMI trajectories measured at multiple time points over the three year RCT. Additional measures collected throughout the study from children and parents will include: bioelectrical impedance; waist circumference; actigraphy; 3-day diet recalls; questionnaires; social network data; and saliva to assess a genetic risk score associated with obesity. RELEVANCE: Pediatric obesity prevention must occur in preschool given that 60% of oven/weight preschoolers will go on to become overweight adolescents. By conducting and testing trials in public community centers, exportable interventions could result allowing for a macro-level system change to address this expanding public health crisis. Read more.

Funding Source: NIH/NHLBI 
PI: Shari Barkin

Long-Chain Fatty Acids, Oxidative Stress and Colorectal Neoplasm Risk

Chronic inflammation is contributors to colorectal carcinogenesis. Eicosapentanoic acid exhibits anti- inflammatory actions while arachidonic acid, an omega-6 polyunsaturated fatty acid, appears pro- inflammatory. Our overarching hypothesis is that individuals with increased dietary ratios of arachidonic acid to eicosapentanoic acid will have an increased risk of colorectal adenoma and that this increased risk is mediated through pro-inflammatory eicosanoids and increased oxidative stress. The specific aims of this research proposal are: 1) To test the hypothesis that a greater erythrocyte phospholipid membrane arachidonic acid to eicosapentanoic acid ratio is associated with an increased risk of colorectal adenomas; 2) To test the hypothesis that an increase in urinary levels of F2-isoprostanes is associated with an increase risk of colorectal adenomas and; 3) To test the hypothesis that a greater arachidonic acid to eicosapentanoic acid ratio is associated with increased levels of prostaglandin E2 and urinary F2-isoprostanes. Read more.

Funding Source: NIH/NCI 
PI: Harvey Murff

O'Brien Center Development: BPH and Obesity

This is toward development of a Center to investigate obesity and BPH.  We conduct two epidemiologic investigations to determine if prostate tissue inflammation or LUTS severity is associated with hypothesized pathways linking obesity to BPH, including increased PGE-M (inflammation), F2-isoprostanes (oxidative stress), and adiponectin and C-peptide (insulin activity).

Funding Source: NIH/NIDDK 
IMPH Faculty: Jay Fowke

Personalized Prevention of Colorectal Cancer

The original version of this application was previously submitted as a R21 application and received a score of 184. To appropriately address the reviewers' suggestions, we are newly submitting this proposal as a R01 application. High calcium intake and magnesium may protect against colorectal cancer and adenoma, however, results have been inconsistent. Although the mean magnesium intake in the US population is similar to East Asian populations with traditionally low risks of colorectal cancer, the ratio of calcium to magnesium is much higher in the US. We reported recently that magnesium intake is related to a significantly reduced risk of adenoma and hyperplasic polyps. This association primarily appeared among those with a low ratio of calcium to magnesium intakes. We have found similar results for calcium intake. The TRPM7 gene is critically involved in calcium and magnesium (re)absorption and homeostasis. We found that the common Thr1482Ile TRPM7 polymorphism significantly interacted with the calcium/magnesium intake ratio in relation to both adenomatous and hyperplasic polyps. Participants who carried at least one 1482Ile allele and who consumed diets with a high calcium/magnesium ratio were at a higher risk of adenoma and hyperplasic polyps than were participants who did not carry the polymorphism. We propose to conduct an intervention trial of 240 participants to investigate the efficacy of modulating the dietary ratio of calcium to magnesium to change markers directly related to tumorigenesis, including apoptosis biomarkers (e.g. TUNEL and Bax), COX-2 (inflammation), Ki-67 (proliferation index), and TRPM7/TRPM6 in colorectal mucosa as well as total erythrocyte magnesium and urinary excretion of prostaglandin E2 metabolite (PGE-M) as primary endpoints. The progressive resistance to apoptosis is one hallmark for almost all cancer types. The apoptosis index is a strong predictor of future adenoma occurrence. The resistance to apoptosis is accompanied by an elevation in COX-2 expression during tumorigenesis. We found in a population-based cohort study that urinary levels of prostaglandin E2 metabolite (PGE-M) were associated with a substantially increased risk of colon and rectal cancers. Urinary level of PGE- M was also elevated among participants with large adenomas compared to those who had either no or small polyps. The primary aims of this study are to conduct a randomized placebo-controlled intervention trial to test whether reducing the calcium to magnesium intake ratio through supplementation of magnesium has effects on the above-mentioned biomarkers. Furthermore, we will examine whether the effect of modulating dietary intake ratio of calcium to magnesium may be more pronounced among those who carry the 1482Ile allele (GA or AA) compared those who do not carry the 1482Ile (GG). If findings from the study are promising, we will propose to conduct a large-scale clinical trial using recurrence of flat, depressed, and polypoid colorectal adenomas or colorectal cancer as clinical endpoints. The results from our study may ultimately help to develop personalized strategies to prevent the occurrence of colorectal adenoma, and, thus, colorectal cancer. Read more.

Funding Source: NIH/NCI
PI: Qi Dai

Pregnancy Folate Status & Early Childhood Respiratory & Atopic Disease Outcomes

The long-term goal of this project is to determine whether maternal folic acid supplementation during pregnancy increases the risk of early childhood asthma and atopy. Supplementation with folic acid, synthetic folate, is recommended during the periconceptional period to prevent neural tube defects (NTD). Studies in different populations have suggested an association between reported folic acid supplementation during pregnancy and increased risk of infant lower respiratory tract infection and early childhood asthma, but data are limited. While adequate intake of folate is essential for prevention of NTDs, it is important to delineate the impact of supplementation on the risk of common respiratory and atopic diseases. Folate plays an important role in DNA methylation, a regulator of gene expression. A causal relationship between folic acid supplementation and respiratory outcomes in children has not been established. However, this relationship does have some biologic plausibility. In a pregnant mouse model, a diet high in methyl donors, including folate, resulted in an augmented allergic phenotype in the offspring, as seen in asthma. Opportunity and Impact. There is no primary prevention strategy for atopic diseases such as asthma. Our objective is to determine whether higher maternal folate intake or the timing of this intake increases the risk of wheezing, asthma, and other atopic diseases in children. This collective work will characterize maternal folate status using objective measures and will assess childhood wheezing, asthma, allergic rhinitis, and atopic dermatitis using validated tools and objective measures. This will be the first investigation in a country with a national fortification program, where individuals may have high intake of folic acid from the diet. Approach. This work will use complementary retrospective and prospective cohorts of mother-child pairs. Specific aim #1 will investigate the population-based incidence of wheezing and asthma during the first 6 years of life, by the timing of folic acid containing prescriptions filled during pregnancy in a retrospective cohort of 80,000 mother-child dyads from the Tennessee Medicaid population. Specific Aim #2 will determine if a) measured maternal plasma folate levels or b) reported folate intake is associated with prospective development of wheezing, asthma, and/or atopy in the first 5 years of life in mother-child dyads enrolled in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) cohort. Innovation and Sustainability. This innovative, cost-efficient project will have the advantages of 1) a well-characterized retrospective cohort with a large number of mother-child dyads and determination of folic acid prescriptions filled by month of pregnancy and 2) a prospective cohort that includes the rich, existing infrastructure of the CANDLE cohort with maternal and infant biospecimens, nutritional data, and prospective follow-up using validated tools and objective measures to assess respiratory and atopic outcomes. This study has potential to inform prenatal recommendations and identify modifiable risk factors for asthma and atopy. Read more.

Funding Source: NIH/NHLBI 
PI: Kecia Carroll

Prevention of Weight Loss in Long Term Care Veterans

This translational research study involves a staff training and management intervention in two VA facilities to improve daily nutritional care practices both during and between meals as provided by routine nursing home staff. Read more.

Funding Source: VA HSR&D Merit Award
PI: Sandra F. Simmons, PhD

Shanghai Breast Cancer Study (SBCS)

The Shanghai Breast Cancer Study (SBCS) is a population-based, case-control study funded by NCI since 1996 to investigate lifestyle factors, genetic susceptibility, and other biomarkers associated with breast cancer risk and survival. Included in the study are approximately 3,500 breast cancer cases aged between 25 and 70 years and an equal number of community controls recruited among female residents of Shanghai, China. In addition to in-person interview data, biological samples were collected from study participants. The resources from the study have supported multiple research and training grants and provided opportunities for many graduate students and postdoctoral fellows to conduct research. To date, over 150 research papers have been published from the SBCS addressing a wide range of significant issues related to dietary, lifestyle, environmental, and genetic contributions to breast cancer risk and prognosis.. Read more.

Funding Source: NIH/NCI 
PI: Xiao Ou Shu

Shanghai Endometrial Cancer Study (SECS)

The Shanghai Endometrial Cancer Study is a population-based, case-control study of 1,204 endometrial cancer cases and 1,212 controls who were aged between 30 and 69 years and recruited between 1997 and 2003. The study recently recruited an additional 587 endometrial cancer patients. The major objectives of the study are to evaluate the role of and interactions between hormonal, dietary, and other lifestyle factors and genetic susceptibility in endometrial carcinogenesis. In addition to detailed dietary intake and other questionnaire-based information, the study also collected a blood or buccal cell sample and a urine sample from participants. The study has published multiple papers reporting novel findings on dietary risk/protective factors and genetic susceptibility factors. The SECS is one of the largest epidemiological studies of endometrial cancer and is a major contributor to the international Epidemiology of Endometrial Cancer Consortium. Read more.

Funding Source: NIH/NCI
PI: Xiao Ou Shu

Shanghai Men's Health Study

The Shanghai Men’s Health Study (SMHS), funded by NCI since 2001, is a population-based cohort study of 61,482 men aged between 35 and 75 years and recruited from 2002 to 2006. At baseline, detailed information on dietary intakes, personal habits, occupational history, medical history, and other lifestyle factors was collected, and anthropometrics were measured. Blood or buccal cell, and  urine samples were collected from 89% of participants. The cohort has been followed through multiple in-person surveys to update exposure information and through record linkages with the population-based Shanghai Cancer Registry and Shanghai Vital Statistics Registry to obtain information on cancer occurrence and survival status. Over the years, SMHS data and biological samples have been used to evaluate many important etiologic hypotheses addressing the contributions of environmental, dietary, lifestyle, and genetic exposures to the development of cancer and other chronic diseases. The cohort supports multiple studies, including over 25 consortium projects. Read more.

Funding Source: NIH/NCI 
PI: Xiao Ou Shu

Tailoring Healthy Eating and Physical Activity for African American Men

Despite increased attention to minority health needs, African American men have higher rates of developing and dying from many diseases associated with unhealthy eating and physical inactivity when compared to white men, white women and African American women. Unfortunately, much of what we know about African American health, including strategies considering culture when targeting healthy eating and physical activity, is based predominately on programs conducted with African American women. This is a significant limitation because well documented, gender-specific differences in dietary health and physical activity highlight the relevance of gender as a determinant of health behavior. Thus, if we are to adequately address the health needs of African American men, both culture and gender must be considered when developing and implementing strategies to increase their healthy eating and physical activity. The aim of this proposal is to develop and test gendered, culturally and contextually relevant messages that will be used in a future, web- based tailored intervention to increase healthy eating and physical activity in African American men. A tailored intervention - that is, an intervention customized to the unique preferences, interests and contexts of individual African American men - may be more engaging than an intervention targeted to African American men as a population group in part, because it may be deemed more personally relevant. In addition, by addressing multiple health behaviors - healthy eating and physical activity - this study reflects the fact that most U.S. adults engage in 2 or more unhealthy behaviors, which puts them at the greatest risks for chronic disease, disability, and premature death. Addressing multiple behavior changes increases the real-world applicability of this research and enhances the chances to uncover common mechanisms of health behavior and unique mechanisms for health behavior change. Our proposed study includes 3 phases: (1) formative research to refine our understanding of gendered, cultural and environmental determinants of healthy eating and physical activity; (2) develop tailored health messages to promote healthy eating and physical activity for African American men; and (3) test and refine the messages to yield a bank of messages for use in future, tailored health promotion interventions to promote healthy eating and physical activity for African American men. Upon completion, we will be well positioned to implement an R01 for a randomized controlled trial to test the efficacy of the tailored messages in a web-based intervention to improve African American men's healthy eating and physical activity. Read more.

Funding Source: NIH/NIDDK
PI: Derek M. Griffith