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Children's Nutrition Research Center

Houston, Texas

Children's Nutrition Research Center - CNRC
USDA/ARS Children's Nutrition Research Center
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Current Research of Postdoctoral Training Faculty

Postdoctoral trainees may participate in any area of ongoing research provided the project chosen is adequately funded and can be completed within a two-year period. Most faculty members suggest a discrete portion of a larger project that the trainee can pursue as his or her own research project.

Kjersti Aagaard-Tillery, M.D., Ph.D.

Perinatal Genomics, Epigenomics, Metagenomics and Discovery Based Translational Science
Dr. Aagaard's experience is uniquely suited to mentorship in research, as it includes experience in multicenter clinical trials focusing on perinatal disorders and utilization of samples and biologic specimens acquired from these trials in high-throughput capacities (e.g., with the NICHD Maternal Fetal Medicine Units Network, the Human Microbiome Project, the FaSTER trial, and the National Children's Study).

She is fully funded in epigenomics and metagenomics translational and basic research in both human and non-human primate translational models and is the recipient of the NIH Directors's New Innovator Award, NCS formative research, the Burroughs Welcome Fund Preterm Birth Initiative, and multiple NICHD and NIDDK R01 and K awards. Dr. Aagaard has received formal training as both a doctoral and postdoctoral fellow in the basic sciences, as well as a Masters in Clinical Investigation through the University of Utah K30 program. She has over 15 peer-reviewed publications on her clinical research, and the remaining over 20 publications constitute translational and bench-top focused research. Dr. Aagaard is allotted 75% protected research time in her fully-salaried position at BCM. Her remaining 25% time is spent as a practicing Maternal-Fetal Medicine specialist. Her research focuses on understanding the genomic and epigenomic mechanisms underlying the developmental origins of adult disease, alongside efforts on metagenomics with respect to the perinatal microbiome. She has a focused interest on maternal high fat diet exposure and the fetal epigenome in non-human primates, alongside maternal tobacco use and placental/fetal epigenomics in relation to human health and disease. She has one of the few laboratories currently conducting front line metagenomics research on the human perinatal microbiome, and serves on the Data Analysis Working Group (DAWG) for the Human Microbiome Project.

With respect to the database functioning and sample acquisition, Dr. Aagaard is PI of the PeriBank, a fully integrated universal database and perinatal biospecimen repository under implementation at Baylor and with St. Luke's Episcopal Hospital/TCH Pavilion for women and Ben Taub Hospital. In addition to banking samples (maternal, paternal, cord blood, placenta) on over 7,000 deliveries/year, over 1800 datafields of information is abstracted and stored back for imputation in analyses such as those anticipated translational research. These datafields include maternal and paternal information, antepartum, intrapartum, and postpartum comorbidities, and neonatal and postnatal data.

Tom Baranowski, Ph.D.

My research is directed toward understanding why children eat the foods and engage in the physical activities they do, as well as designing and evaluating programs to help change these dietary and physical activity behaviors. Areas of interest include fruit, juice, vegetable (FJV) and water consumption, obesity prevention, and physical activity.

I believe the simple energy balance model is inadequate to understand the obesity epidemic, and am searching for biological variables to complement behavioral variables (e.g. satiety processes) in understanding factors leading to child obesity. Differences in these phenomena among major ethnic categories are of particular interest, as are innovations in their measurement.

I am principal investigator for six research grants: the Pediatric Type 2 Diabetes Mellitus Prevention Program –the HEALTHY trial (a multi-site U01 grant for research among middle school students funded by the National Institute of Diabetes and Digestive and Kidney Diseases); the development and evaluation of two video games for diabetes prevention –"Escape from Diab" and "Nanoswarm: Invasion from Inner Space" (funded as an SBIR grant by the National Institutes of Diabetes and Digestive and Kidney Diseases); the role of genetically determined PROP sensitivity in the development of obesity among ethnically diverse children (an R01 grant funded by the National Cancer Institute); the development and validation of an interactive computerized 24 hour dietary recall program –FIRRSt4 (funded by the National Cancer Institute); the development of a video game on smart phones using a parent-child simulation to train parents in effective vegetable parenting practices –Kiddio-Food Fight™ (an R21 grant funded by the National Institute of Child Health and Human Development); and the assessment of whether active video games (specifically the Wii) increase physical activity, primarily among children living in unsafe neighborhoods who are not allowed to play outside(an R21 grant funded by the National Cancer Institute). We have a small grant to test Diab and Nano with pediatric cancer survivors (who suffer high rates of obesity) to adapt it to their needs and interests. I am co-investigator on four other funded projects including a walking school bus intervention program; a TV reduction program for preschoolers; an obesity prevention intervention for pediatric primary care; and tests of general versus specific goal setting within a dietary change videogame.

John W. Belmont, M.D., Ph.D.

Dr. Belmont's lab uses high-throughput expression and genotyping to investigate cardiovascular, infectious disease, and nutritional disorders. He and his lab have extensive research projects on the genetic basis of cardiovascular malformations.

For example, they are studying the genetics of hypoplastic left heart and aortic coarctation, the genetic basis of sporadic thoracic aortic aneurysm and defined an early response to seasonal influenza vaccine based on transcriptional signature. They are also systematically characterizing new syndromic forms of cardiovascular malformations using microarray genotyping and copy number analysis, and are collaborators on a project to understand.

A major project involves mapping expression quantitative trait loci that are associated with responsiveness to influenza vaccine. They are mapping gene variants for effects on all transcripts that show interindividual variation in those trials. Dr. Belmont has also developed an interest in medical population genetics. He was a collaborator on the International HapMap Project and with scientists at the Human Genome Sequencing Center helped to produce the data for chromosome 12. In a clinical service project, he designed a genotyping chip called the Personal Medical Genomic Profile (PMGP) offered by the Baylor Medical Genetics Laboratories.

Douglas G. Burrin, Ph.D.

Dr. Burrin's lab has several basic and translational projects designed to establish how nutritional support, enteral versus parenteral, affects gut and liver function and susceptibility to disease in early development.

They have used the neonatal piglet to establish unique models of parenteral nutrition-associated liver disease (PNALD), necrotizing enterocolitis (NEC) and short-bowel syndrome (SBS) to address clinically-relevant problems in pediatric gastroenterology.

Current projects in the laboratory seek to identify the cellular and molecular mechanism that lead to PNALD and metabolic dysfunction associated with prematurity and neonatal parenteral nutrition (PN) support. They are also testing whether the adverse metabolic phenotype induced by PN is programmed and persists beyond the neonatal period and predisposes to adolescent fatty liver disease and type 2 diabetes. Studies also are aimed at establishing the cellular and physiological functions of glucagon-like peptide 2 (GLP-2), an FDA-approved gut hormone currently in clinical trial for treatment of adult short-bowel syndrome.

Current studies are aimed at establishing unique enterally-mediated signaling mechanisms that trigger enteroendocrine cell GLP-2 secretion and GLP-2 receptor function. They are also testing the efficacy of GLP-2 administration for prevention of NEC and treatment of SBS in premature piglet models.

Nancy F. Butte, Ph.D.

The overall goal of Dr. Butte's current research is to identify environmental and genetic determinants of childhood obesity in Hispanic children.

To do so, in-depth phenotyping and genotyping were performed on obese and nonobese Hispanic children and their biological parents. A genome scan was performed on 1600 individuals enrolled in the VIVA LA FAMILIA Study aimed at the identification of genes that have a measurable effect on the expression of childhood obesity and its comorbidities. Further SNP genotyping and DNA resequencing are being used to identify genetic variants that influence quantitative variation in body composition, energy expenditure, physical activity, food intake and eating behavior.

Dr. Butte and her colleagues recently conducted the VIVA LA SALUD Study for weight management in obese Hispanic children at Texas Children's Pediatric Associates clinics serving low-SES families. Studies at local YMCAs are currently underway to evaluate the Mind Exercise Nutrition Do It! (MEND) program for weight management of low income children.

To achieve these research goals, methodologies have been developed to measure energy expenditure, physical activity, and body composition in the populations of interest; these include room and portable respiration calorimeters, the doubly labeled water method for the measurement of free-living total energy expenditure, body composition multicomponent models, and sophisticated models for the prediction of physical activity and energy expenditure using wearable activity and heart rate monitors in children.

Karen Weber Cullen, DrPH, RD, LD

Dr. Cullen's major research focus is on pediatric nutrition and obesity prevention. Her current funded projects include the development and evaluation of a website on healthy eating and physical activity for high school students (USDA); the evaluation of a web-based program on healthy eating for African-American families (R01); a pilot study to improve elementary school cafeteria promotion of fruit, vegetables and whole grains via parent messaging and cafeteria marketing (USDA), and a study to assess the impact of the proposed new guidelines for school meals on student consumption and cost (R01).

Jayna Dave, Ph.D.

Dr. Dave's research is directed towards prevention of obesity and obesity-related chronic diseases such as cancer, cardiovascular diseases, and diabetes in low-income food-insecure populations, primarily focusing on nutrition and health disparities.

Her current research focuses on alternative food assistance programs such as food banks and their potential to provide nutrition education and healthy foods to the low-income food-insecure clients.

Her current NIH funded projects as a principal investigator include: 1) To assess the impact of the Kids Café program (national feeding program) on children's dietary behaviors and nutrition knowledge (R03); and 2) To investigate the potential of food banks to integrate nutrition education for obesity and cancer prevention into their usual operations using community-based participatory research (CBPR) principles (R21).

Teresa A. Davis, Ph.D.

The long-term objective of Dr. Davis's research is to identify the mechanisms by which nutrients, hormones, and growth factors regulate protein deposition in skeletal muscle of the neonate.

Her lab has shown that the high rate of protein accretion in the neonate is due to the elevated response of protein synthesis to nutrient intake, which is particularly profound in skeletal muscle. Using novel pancreatic-substrate clamps, which were developed to allow independent control of plasma amino acids, glucose, and insulin, her lab demonstrated that the feeding-induced stimulation of protein synthesis involves independent regulation by both insulin and amino acids in skeletal muscle, and to be mediated by amino acids in visceral tissues.

Recent studies are identifying components of the intracellular insulin and nutrient signaling pathways that regulate the high rate of muscle protein synthesis in the neonate. The role of individual amino acids, particularly the branched-chain amino acid, leucine, as nutrient signals to regulate translation initiation is also being explored.

Future research will examine the efficacy of a novel functional amino acid supplement to improve protein anabolism. Another focus of Dr. Davis' research is to determine the impact of different feeding modalities on protein synthesis, degradation, and deposition in skeletal muscle of the neonate. The work is contributing valuable information to improve strategies for the nutritional management of infants and children and to improve animal production.

Marta L. Fiorotto, Ph.D.

The primary focus of our research concerns the long-term consequences of impaired muscle growth in early life. Previously, we documented that growth of the immature muscle is higher than at any other time in life and is mediated by the enhanced sensitivity of anabolic processes to nutrients and growth factors.

One consequence of impaired muscle growth during this early phase of rapid growth (as occurs when there is an inadequate supply of nutrients) is that it chronically and permanently compromises muscle mass. We are using state-of-the-art molecular, cellular, and imaging techniques, to understand the mechanisms responsible for this programming of adult muscle mass by early life experiences. Using in vivo nutritional manipulations in normal and transgenic mice, we are attempting to define the precise window of development during which the programming of muscle mass occurs and to establish the mechanisms that are responsible.

To accomplish this, we are evaluating how the interaction of age and diet modulate both extrinsic and intrinsic factors that regulate satellite cell function and muscle fiber protein metabolism. Our ultimate goal is to use the information gained to develop interventions that could be implemented to reverse this early deleterious programming of muscle mass.

A secondary focus of the lab is to assess the metabolic consequences of muscle regeneration and to determine how this affects the nutrient needs of the organism. We are using the mdx mouse, a model for Duchenne Muscular Dystrophy, to define how high levels of muscle regeneration impact whole body energy expenditure and protein turnover. The studies employ our extensive mouse metabolic facility to quantify total energy expenditure, and its individual components, activity, food intake, whole body and individual tissue protein turnover, and body composition. Such information will enable us to better define optimal diets for sustaining individuals with extensive muscle pathology.

Michael A. Grusak, Ph.D.

Dr. Grusak's laboratory's long-term goals are to characterize the dynamics of nutrient flow within plants in order to determine the biophysical and molecular signals that regulate source-to-sink nutrient partitioning, and ultimately to use this information to enhance the nutritional quality of plant foods for human consumption.

The enhancement of staple crops, especially those consumed by women and children in developing countries, is of special concern. His group's current focus is on the minerals iron, zinc, calcium, and magnesium, as well as various nutritional or health-beneficial classes of phytochemicals such as carotenoids and flavonoids.

Dr. Grusak works with various seed crops such as rice, wheat, maize, soybean, bean, pea, and chickpea; vegetable crops, such as tomato, spinach, lettuce, and collards; and the model plants Medicago truncatula, Lotus japonicus, and Arabidopsis thaliana. Research studies range from the whole-plant to the molecular levels; these studies include mineral analyses, enzyme kinetics, gene discovery and gene expression investigations, as well as quantitative genetics methods.

With regard to his human nutrition research, his lab has developed hydroponic growth facilities and various gas atmosphere labeling protocols to intrinsically label plant foods with stable isotopes of important elements; these are then used to assess nutrient bioavailability and metabolism in humans.

Xinfu Guan, Ph.D.

Dr. Guan's research goals are to [1] understand the cellular and molecular mechanisms by which nutrients and hormones interact to control the gut growth and function; and influence energy balance and glucose homeostasis.

Using glp2r knockout mice, he wanted to define the physiological function and signaling network of glucagon-like peptide-2 (GLP-2) receptor that controls intestinal epithelial growth, absorption and microcirculation; and regulates energy balance and glucose homeostasis. Dr. Guan's laboratory has demonstrated that GLP-2 receptor activation in the hypothalamus is essential for glucose homeostasis by modulating electric activities of POMC neurons. Dr. Guan's another goal is to [2] determine the physiological significance of CNS vs. peripheral GLP-1 receptor activation in the control of glucose homeostasis and energy balance using glp1r knockout mice. Metabolic surgery (RYGB) improves glucose homeostasis prior to significant loss of body weight, and enhances secretion of GLP-1/2. Thus, Dr. Guan's final goal is to [3] elucidate GLP-1/2-mediated neuroendocrine roles in glucose homeostasis and insulin sensitivity following the RYGB. Dr. Guan has established stable isotopic tracer techniques to assess nutrient uptake and metabolism by the gut, and quantify insulin sensitivity and glucose homeostasis during hyperinsulinemic euglycemic clamp. In addition,

Dr. Guan has used electrophysiological approaches (e.g. the whole-cell patch clamp) to determine activities of ion channels underlying GLP-1/2-induced neuronal action. Together, the elucidation of GLP-1/2 neuroendocrine role in the control of energy balance and glucose homeostasis may reveal novel targets for the treatment of intestinal dysfunctions, obesity and diabetes.

Darryl L. Hadsell, Ph.D.

Dr. Hadsell's lab uses state-of-the-art immunohistochemical and imaging techniques along with genomic and proteomic strategies to determine the relationships between in-vivo developmental processes that occur in the lactating mammary gland and the gene expression and metabolic events that regulate them.

The regulation of mammary cell turnover function during lactation involves interactions between signaling pathways that regulate cell cycle progression, cell differentiation, cell metabolic rate, and cell death. These interactions are not simply events which occur within the secretory epithelial cell, but involve other cell types within the mammary gland as well and regulated not only by the genetic background of the lactating female but also by environmental factors such as age, diet, and body composition.

Dietary strategies along with transgenic and knockout mouse models are used to determine the impact of perturbing specific signaling or metabolic pathways on the regulation of postpartum mammary cell turnover.

The lab's work on IGF-I action suggests that variation signaling pathway use by the IGF-I receptor (Igf1r) occurs at different developmental stages: inhibit mammary cell apoptosis during lactation and cell proliferation during earlier stages of development. The regulation of apoptosis in the lactating secretory cell is known to involve intrinsic regulation through the mitochondria.

Dr. Hadsell's recent studies on mitochondrial biogenesis and function in the mammary gland suggest that oxidative damage to secretory cell mitochondria may play a significant role in causing the decline in milk synthesis capacity that occurs with progression through lactation. Using genome-wide association and microarray analysis, he hopes to identify gene pathways that regulate the loss of milk synthesis capacity known to occur during prolonged lactation and maternal obesity.

Morey W. Haymond, M.D.

Dr. Haymond's lab continues to study the factors that affect and regulate whole body substrate metabolism, particularly in children with obesity and hyperglycemia using classical metabolic techniques.

More recently, interest has focused on the factors which impact maternal metabolism during the immediate post partum period and during established lactation. Successful human lactation is associated with a number of beneficial outcomes for both the mother and the infant. Women who breastfeed have lower risk of obesity, type 2 diabetes, hyperlipidemia and hypertension.

Aside from primary lactation failure, obese women, mothers of premature infants and teenage mothers all struggle with breastfeeding and successful lactation. The lab has determined the impact of milk production of maternal glucose, fat and protein metabolism, and has recently developed the methodologies to measure serially gene expression in the mammary epithelial cells in humans from isolated RNA in the milk fat globules of human milk and have explored the impact of feeding, fasting and rhGH therapy.

The lab is now determining the ontogeny of gene expression, protein production and nutrient content using expression micro arrays, and proteomics, and exploring the nature and potential role of micro RNAs in normal women and those listed above who struggle with successful lactation to determine the pathophysiology of the defect in milk production.

William C. Heird, M.D.

Dr. Heird's research concerns the needs for specific nutrients during infancy.

His previous research concerning fatty acid needs has helped establish that both term and preterm infants can convert the 18-carbon precursors of ω6 and ω3 fatty acids to longer chain, more unsaturated fatty acids and has helped clarify the metabolic steps involved. Current studies in this area concern the mechanisms of incorporation of these fatty acids into brain vs. other tissues, including the role of tissue-specific expression of ∆-6 and ∆-5 desaturases.

Current research concerning protein needs of low birth weight (LBW) infants addresses the hypothesis that there is a finite period during early infancy during which the infant can optimally use protein for growth and that failure to provide sufficient protein intake during this period contributes to the inadequate growth of these infants. This research also will define this finite period and determine if providing a higher protein intake during early infancy improves growth and neurodevelopmental outcome of these infants. Collaborators in this area of research include members of the Meyer Center for Developmental Pediatrics.

Kendal Hirschi, Ph.D.

Dr. Hirschi's lab studies model systems biology in plants, yeast and mice, and perform translational research related to agricultural improvement.

At the molecular level, the goals are to understand the structure, biological function, and regulation of transporter proteins that control trafficking into and out of the vacuole. Many of their molecular approaches use the standard genetic "tool kit".

Another major goal is to learn how to manipulate the expression and function of these transporters to increase the nutritional content of crop plants, improve plant productivity, and cleanse polluted soils. Obtaining help from nutritional scientists at theVegetable and Fruit Improvement Center at Texas A&M, they perform clinical trials addressing how changes in plant architecture alter nutrient bioavailability. Using a combination of approaches, they are attempting to characterize the expression and physiological function of these transporters.

Additionally, they will use these ion transporters as "bait" in a series of genetic approaches in yeast and plants to identify the molecules that interact with these transporters and, thus, regulate ion homeostasis. Once they have characterized and identified the ensemble of ion transporters and their regulatory molecules, they can begin to manipulate ion storage, signal transduction events, and the environmental constraints of traditional agricultural practices.

Sheryl O. Hughes, Ph.D.

The overall goal of Dr. Hughes' research is to study the influence of parent-child interactions on child eating behaviors and weight status.

Dr. Hughes' previous research with low-income Head Start families included the development of the Caregiver's Feeding Styles Questionnaire (a parent report feeding measure of authoritative, authoritarian, indulgent and uninvolved types of parents) and observations of parent-child interactions during the dinner meal.

Observations include measures of parent affect, behavioral feeding practices, and the emotional climate of the dinner meal in low-income families. Ongoing research includes an investigation of the influence of parenting on the development of children's self-regulation of food intake and the development of a parenting intervention to teach parents to be more aware of satiety cues during eating occasions. Observations from parent-child interactions in Head Start families will be used to inform the intervention.

Farook Jahoor, Ph.D

Dr. Jahoor's research focuses on the modifications of macronutrient metabolism in conditions such as diabetes mellitus, overweight and obesity, severe protein-energy malnutrition, acute and chronic infections, sepsis, pregnancy and ageing and how these modifications impact other aspects of physiological function and aspects of host defense, in particular, the capacity to synthesize the antioxidant glutathione and the acute phase proteins.

The goal is to determine how these changes in turn precipitate other pathologies, and to use the metabolic information obtained to design novel therapeutic strategies to counter these derangements. To achieve these goals current research efforts utilize stable isotope tracer methodologies and a combination of animal models and patient populations.

Ongoing research centers on: 1) The alterations of protein, lipid and glucose metabolism in sepsis and COPD; 2) Lipid and protein metabolism in HIV infected individuals with lipodystrophy; 3) Sulfur amino acid metabolism and glutathione homeostasis in the pathogenesis of Kwashiorkor; 4) Aromatic amino acid metabolism in children with severe childhood undernutrition. 5) Determination of how maternal obesity and undernutrition and sub-clinical folate and vitamin B12 deficiencies alter the metabolic/physiologic adaptations necessary for a successful pregnancy; 6) Role of nitric oxide synthesis in the hypotension of sepsis and of idiopatic pulmonary hypertension.

Brendan Lee, M.D., Ph.D.

Dr. Lee's research is focused on translational research in structural birth defects affecting the skeleton and inborn errors of metabolism.

In his studies on human skeletal dysplasias, skeletal development, and skeletal homeostasis, he studies the regulation of morphogen signaling (TGFβ and Notch), transcriptional mechanisms (Runx2, Trps1, and Sox9), and matrix homeostasis (collagen prolyl-hydroxylation).

A unifying approach has been to first elucidate the developmental pathways that cause in human and mouse osteochondrodysplasias and then to determine their contributions to more common pathologies such as osteoporosis, osteoarthritis, and cancer. In his studies on biochemical genetic disorders, he has focused on urea cycle disorder as models of complex disease involving nitric oxide dysregulation. He has also attempted to develop cell and viral gene therapy for these conditions (urea cycle disorders, hyperbilirubinemia, hemophilia, and osteoarthritis).

Loning Fu, Ph.D.

Dr. Fu's laboratory studies the role of circadian homeostasis in cancer prevention and treatment using molecular, cellular and genetic approaches.

Self-rotation of the earth results in alternating changes in the light/dark condition over a 24 hour period. Such changes impose a strong selection during the evolution. As a result, most physiological processes in mammals follow a circadian rhythm that is generated by an endogenous circadian clock. Disruption of circadian rhythm has been linked to increased risk of metabolic dysfunction and cancer.

Our study is to understand 1) how the circadian clock couples metabolism with cell division in vivo, 2) whether disruption of circadian homeostasis of cell proliferation and metabolism synergistically promotes hepatocellular carcinoma development, and 3) the role of circadian rhythm of liver metabolism in anticancer therapy. Our studies will lead to developing novel strategies for cancer prevention and treatment.

Jason A. Mendoza, M.D., MPH

Dr. Mendoza's research portfolio includes obesity prevention projects in children with a focus on minority and socioeconomically disadvantaged groups.

He leads the design, implementation, and evaluation of community and school-based behavioral interventions aimed at improving nutrition, reducing sedentary activities, or improving physical activity in children. Interventions include the "Walking School Bus," an integral part of the Safe Routes to School program, and the "Fit 5 Kids" television reduction curriculum. He has developed and validated questionnaires related to these interventions. Dr. Mendoza also leads studies aimed at identifying risk factors for obesity and related disorders in children and adults using nationally representative databases such as the National Health and Nutrition Examination Survey. To support these efforts, he has been the principal investigator on several grants from the NIH, the Robert Wood Johnson Foundation, and other institutions.

David D. Moore, Ph.D.

The 48 members of the nuclear hormone receptor superfamily function as ligand-dependent or, in some cases, ligand-independent transcription factors. The major goal of this laboratory is to understand the roles of the newer members of this superfamily, particularly their impact on metabolic and oncogenic pathways in the liver.

One major focus is on CAR, which functions to regulate the response of the liver to xenobiotics, potentially toxic foreign compounds. Activation of CAR by specific xenobiotic stimuli, and also by toxic endogenous compounds such as bile acids and bilirubin, increases the liver's ability to metabolize and eliminate them.

CAR-dependent responses are generally protective, but can be deleterious. Thus, chronic activation of CAR by non-genotoxic carcinogens results in liver tumors, due to direct effects of CAR on both hepatocyte proliferation and apoptosis. We are pursuing both the mechanism of this tumor promotion and therapeutic approaches that block it. We are also examining the linkage of CAR to metabolic diseases and have found that it is activated by type 1 diabetes, and also that its activation by xenobiotics has a beneficial effect in type 2 diabetes.

FXR is the primary nuclear receptor for bile acids, cholesterol metabolites that are important regulators of lipid homeostasis. FXR regulates a number of key metabolic target genes including SHP, an unusual orphan receptor that lacks a DNA binding domain. SHP represses transactivation by several other nuclear receptors and decreases expression of target genes, including the rate limiting enzyme for bile acid production. We have found that FXR null mice are insulin resistant, due at least in part to elevated levels of circulating free fatty acids. Bile acids can promote liver growth, and we have found that FXR activation is essential for normal liver regeneration. Bile acids can also act as tumor promoters, and we are studying the basis for spontaneous tumorigenesis in double knockout mice lacking both FXR and SHP, which have severe liver toxicity due to uncontrolled bile acid production. We will continue to use pharmacologic and mouse knockout approaches to explore the diverse metabolic regulatory functions of the nuclear hormone receptors.

Paul A. Nakata, Ph.D.

Dr. Nakata's primary research interest concerns the mechanisms regulating nutrient partitioning in plants and the manipulation of these mechanisms for nutritional improvement of plant foods.

His current research focuses on understanding the mechanisms regulating calcium partitioning and sequestration within plants. This research employs an integrated biochemical, cellular, molecular, and genetic approach to identify and characterize the components regulating calcium transport and storage. Such studies should lead to the rational design of strategies to enhance calcium abundance and bioavailability in plant foods.

Theresa A. Nicklas, DrPH

Dr. Nicklas's research interests encompass both the epidemiological and intervention aspects of chronic disease prevention and health promotion.

Specifically, how do eating behaviors and other lifestyles influence the development of chronic disease risk factors early in life? Also, what are the behavioral factors influencing the development of adverse lifestyles early in life? Areas of interest include: environmental factors influencing the development of eating patterns early in childhood; how these eating patterns relate to the onset of obesity, cardiovascular disease, cancer and type 2 diabetes; and effective intervention strategies for changing and maintaining healthful behavior changes, particularly in children and adolescents. A current area of research involves a detailed investigation of the relationship between eating patterns and obesity in children and young adults. Planned studies include an examination of family and caregiver influence on eating behaviors of preschool children from different ethnic groups; a family-based intervention program for prevention of obesity; and a longitudinal study investigating factors that influence the development of eating patterns early in childhood, and determining whether these eating patterns track into adulthood.

Teresia O'Connor, M.D., MPH

Dr. O'Connor's research focuses on understanding how parents influence their children's obesity-related behaviors through the framework of parenting styles and parenting practices in order to identifying strategies to best prevent and treat childhood obesity.

For example her recent work (1) helped identify how food related parenting practices used in combination effect low-income preschool children's fruit and vegetable intake, in order to develop a more comprehensive measure of food parenting; (2) investigated health and nutrition professionals' perceived effectiveness of parenting practices intended to promote fruit and vegetable intake in children, across 6 countries; and (3) assessed the feasibility of an Obesity "Prevention Plus" intervention (Helping HAND ) for pediatric primary care clinics targeting children 5-8 years old, along with their parent's behavior-specific parenting practices. She is the PI on an on-going NICHD funded project (1 R21 HD060925) to investigate parenting and neighborhood environmental influences on Hispanic preschool children's physical activity.

Monique Rijnkels, Ph.D.

Dr. Rijnkels' primary research interest is the to understand the underlying mechanisms through which lactation is established, maintained and variation in mammary function arises.

The mammary gland is a highly specialized tissue unique to mammals; its primary function is to produce specialized neonatal nutrition–milk. Furthermore, breast cancer is the second most diagnosed cancer in women and the second leading cause of cancer related death in women. To address crucial aspects of lactation and neonatal nutrition and to better treat and prevent breast cancer a thorough understanding of the development and functioning of the mammary gland is needed.

Dr. Rijnkels' lab focuses on the contribution of epigenetic regulation to the temporal and spatial regulation of genes in the developing mammary gland– including those that lead to cell fate and lineage decisions–and how this relates to function and disease. Dr. Rijnkels' lab employs state-of-the-art Next-Generation-Sequencing based chromatin analysis (Chip-seq, DNase-seq MeDIP /MBDcap) and transgenic mouse models to study epigenetic regulation in the mammary gland.

Jeffrey M. Rosen, Ph.D.

Mammary Gland Development and Breast Cancer The research objectives of the Rosen laboratory are to elucidate the mechanisms regulating the normal development of the mammary gland including the hormonal control of milk protein gene expression, and to determine how these regulatory mechanisms have deviated in breast cancer.

His laboratory is studying the role of systemic hormones, specifically prolactin, glucocorticoids, estrogens and progestins, and local growth factors, including members of the Wnt, Fgf and IGF families, on these processes. The role of specific transcription factors and their dominant-negative isoforms, including members of the C/EBP, Stat and NF I families, are also being examined using transgenic and knockout mouse models. Postnatal mammary gland development is being studied in knockout mice displaying late embryonic or neonatal mortality by transplantation of mammary epithelium into the cleared mammary gland fat pad of syngeneic recipients. Genetically engineered mice, coupled with FACS analysis and transplantation into the cleared mammary fat pad, have also been employed as model system in which to isolate and characterize functional mammary stem/progenitor cells. Transgenic and knockout mouse models are being used to elucidate changes in normal mammary gland stem cells and progenitors and signal transduction pathways that are involved in the progression from the normal mammary gland to preneoplasias, as well as the role of mutant p53 and Chk1 in genomic instability and the development of aneuploidy. These studies are being translated into the clinic to understand the mechanisms of therapeutic resistance of cancer stem cells to chemotherapy and radiation. Finally, studies are underway to elucidate the mechanisms by which noncoding RNAs regulate mammary gland development and are altered in breast cancer.

Lanlan Shen, Ph.D.

My laboratory is focused on understanding the developmental origins of cancer from an epigenetic perspective.

We are specifically interested in the fundamental mechanisms regulating DNA methylation during both development and cancer pathology. Using genome-wide DNA methylation profiling, my laboratory was among the first to recognize the role of programmed promoter CpG island methylation during normal development. Interestingly, hypomethylation and reactivation of these genes were observed in cancers, suggesting a link between developmental dysregulation and carcinogenesis. We are now characterizing epigenetic methylation changes as a developmental programming event in the path from stem cells to differentiated cells to tumor cells. We are developing a targeted knock-in mouse model to determine if, during critical developmental periods, specific nutrients related to one-carbon metabolism can modulate not only promoter hypermethylation, but also consequent epigenetic silencing and enhanced susceptibility to diseases. This research will provide novel insights into the fundamental processes of development and how these processes are influenced by diet, nutrition and other factors.

Robert Shulman, M.D.

Dr. Shulman's primary research interest concerns the function and adaptation of the gastrointestinal (GI) tract in children.

His laboratory focuses on functional GI disorders in children to learn how the gut interacts with, affects and is affected by diet, the immune system, the peripheral and central nervous systems, and psychological functioning. His research group uses a multidisciplinary approach involving collaboration between basic scientists, clinicians, and psychologists. Current studies include: Investigation of the interaction between diet, the gut microbiome, and GI function; Study of the effects of dietary fiber and probiotics on GI function; and investigation of the contribution of psychological factors to the perception of GI function.

C. Wayne Smith, M.D.

Dr. Smith's research focuses on inflammation and wound healing, the mechanisms of leukocyte accumulation at sites of inflammation and tissue injury, and the influence of dietary factors on these processes.

A model of ocular surface injury (simple corneal abrasion) is used to induce an inflammatory response to injury. Intravital microscopy allows direct visualization in real time of the inflammatory events in the cornea and in other vascular beds that are directly accessible to observation. The use of knockout and transgenic mice, blocking monoclonal antibodies, and targeted inhibition allow analysis of molecular mechanisms. Studies of the influence of dietary factors on the inflammatory process are currently limited to the effects of high fat diets in murine models. Using insights from the basic research on inflammation, cytokines, chemokines, leukocyte changes, adhesion molecules, toll-like receptors and injury in tissues of mice fed diets high in milk fat ("Western diet") or corn oil and high sucrose are addressed. These studies focus on pro-inflammatory and anti-inflammatory changes in adipose tissues, liver, blood, and corneal wound responses.

E. O'Brian Smith, Ph.D.

Dr. Smith provides statistical support to CNRC investigators and postdoctoral fellows.

He is available to assist investigators and postdoctoral fellows in the biostatistical aspects of research including formulation of the research question, appropriate study design, sample size estimation, data collection and management, data analysis, computer applications, preparation of research proposals and manuscript preparation. He also provides a series of didactic lectures on research design, analysis and methods of data analysis as part of the required course, "Fundamentals of Clinical Research".

Yuxiang Sun M.D., Ph.D.

Dr. Sun's research interests are nutritional regulation, glucose- and energy-homeostasis, and the pathophysiology of obesity, diabetes and aging.

The incidences of obesity and diabetes have reached epidemic proportions in the United States. The primary cause of diabetes is insulin resistance, which is a common consequence of adiposity. Ghrelin is the only circulating orexigenic hormone known to stimulate appetite and promote obesity. Dr. Sun generated knockout mice for ghrelin and the ghrelin receptor (GHS-R). Dr. Sun's laboratory was the first to discover that the suppression of ghrelin improves pancreatic beta cell function, and that suppression of GHS-R improves thermogenesis thus increasing energy expenditure and enhances insulin sensitivity. Her work has established that ghrelin and GHS-R are important players in diabetes. The current objective of Dr. Sun's laboratory is to further elucidate the cellular and molecular mechanisms of ghrelin/GHS-R in obesity and diabetes. Her lab will focus on following specific areas: 1) to study the roles of ghrelin signaling in pancreatic islet function; 2) to investigate the roles of ghrelin signaling in central glucose sensing and peripheral insulin sensitivity; 3) to assess the role of GHS-R in adipose inflammation and impairment of thermogenesis; 4) to identify and understand the dietary risk factors for type 2 diabetes. Physiological, pharmacological and immunological approaches will be carried out in global and tissue-specific knockout mice, as well as in primary and cell culture systems. The ultimate goal of Dr. Sun's laboratory is to advance the understanding of genetic and environmental causes of obesity and diabetes, to help provide better nutritional guidelines, and to develop new therapeutic approaches for their prevention and/or treatment.

Debbe Thompson, Ph.D.

Dr. Thompson's research focuses on three separate but related, areas: the design, development, and evaluation of digital media (e.g., web-based programs; video games); health message design; and theory and measurement of youth diet and physical activity behavior.

All three research areas emphasize youth obesity prevention through the promotion of positive behaviors, such as consuming more fruit, vegetables, and water and being more physically active and less physically inactive. Emerging interests include examining the neural effects associated with food choice behavior; promoting the use of behavioral theory and techniques in the design of serious videogames for health; and identifying methods for enhancing logon rate to web-based behavior change interventions for youth.

Qiang Tong, Ph.D.

Dr. Tong's lab studies the molecular mechanism of caloric restriction and Sirtuin function.

Dietary caloric restriction is the only known non-genetic method to extend animal life span. It also reduces the onset of age-related diseases, such as obesity, diabetes, cancer, neurodegenerative and cardiovascular diseases. The study of the molecular mechanism of caloric restriction may lead to pharmaceutical treatments that mimic dietary restriction's beneficial effects. Sir2 gene, which encodes NAD-dependent deacetylase, was found to mediate the effect of caloric restriction on life span extension in yeast, C.elegans and fruit flies. His lab is investigating how mammalian Sir2 homologues, Sirtuins, regulate cellular functions and animal metabolism, suing cell culture and mouse models with genetic engineered Sirtuin genes. Another research direction of his lab is to study the adipose tissue function. By investigating how mature adipocytes are derived from multipotent stem cells, one will gain insights into obesity development and prevention. In addition, by studying how fat metabolism and its endocrine secretion influence whole body metabolism, one will learn how obesity leads to insulin resistance and subsequent type-2 diabetes.

Ignatia Van den Veyver, M.D.

Dr. Van Den Veyver's laboratory focuses on three areas.

The first is the study of complete hydatidiform moles (CHM), an abnormal development of human pregnancy with a hyperplastic placenta and no fetus. Most sporadic CHM are diploid androgenetic and their entire genome is paternally inherited. Rare recurrent HM have a normal biparentally inherited diploid genome (BiHM), but show a generalized defect of reprogramming of imprinting. The women who have the BiHM pregnancies have autosomal recessive mutations in NLRP7 on chromosome 19q13.4. They are focusing on characterizing the function of NLRP7 to understand how it can lead to disturbances of imprinting, BiHM and other reproductive failure and to find new imprinted genes that have placenta-specific imprinting. In a second area of investigation, they are focusing on the identification of the genes mutated in Aicardi syndrome (AIC) and Goltz syndrome or focal dermal hypoplasia (FDH), two severe X-linked disorders that only or primarily affect girls. They are collecting DNA samples from patients with FDH to search for the mutated gene by mutation analysis of candidate gene and by comparative genomic hybridization on DNA microarrays. They have discovered that PORCN, encoding the human homolog of Drosophila porcupine, which is essential for secretion of Wnt proteins, is the gene that is mutated in FDH and are now embarking on the functional analysis of the consequence of mutations in PORCN using animal models. Finally, they are investigating the epigenetic gene regulation during development. They are determining in mice whether DNA methylation gene expression, and long-term health and disease can be influenced by diets given at different stages of development.

James Versalovic, M.D., Ph.D.

The Versalovic laboratory seeks to understand the nature of the human metagenome, the microbiome and how microbial communities impact human gastrointestinal health and disease.

The primary topics of interest in terms of gastrointestinal physiology and disease are mucosal immunity, inflammation, nutritional genetics, and the enteric nervous system. The laboratory is deeply engaged in the development of new strategies to characterize the composition and dynamics of the human microbiome. Refinement of DNA sequencing and microarray-based approaches are being deployed to understand the nature of mucosal-associated microbial communities. Currently, the lab is trying to characterize the intestinal microbiome and the nature of the core microbiome in healthy children. In parallel, it is also studying the changes in the metagenome that may be associated with disorders of mucosal inflammation and recurrent abdominal (visceral) pain. The tools for analysis include next-generation DNA sequencing, quantitative PCR and high density microarrays to study shifts in the the metagenome and human-associated microbial communities. New projects are being developed for exploration of changes in the mammalian microbiome and how the metagenome may help us develop new strategies important for cancer prevention and human nutrition. Already, vitamin biosynthesis and other nutrient pathways have been identified in selected commensal microbes that may have implications for human nutrition.

Robert Waterland, Ph.D.

Research in the Waterland lab aims to understand how nutrition and other environmental influences during prenatal and early postnatal development affect individual susceptibility to various diseases later in life.

Focus is on nutritional influences on developmental epigenetics as a likely mediating mechanism. Epigenetic mechanisms are established during development to stably regulate tissue-specific patterns of gene expression. DNA methylation is of particular interest because mammalian one-carbon metabolism, which supplies the methyl groups for DNA methylation, is intimately dependent on dietary methyl donors and cofactors. They use various mouse models to investigate early nutritional influences on the developmental establishment of DNA methylation and associated phenotypes. Retrospective studies are being conducted in humans to identify persistent epigenetic changes associated with early nutritional exposures. They use genome-wide DNA methylation profiling, bisulfite pyrosequencing, and various gene expression assays. They are also investigating the role of epigenetic dysregulation in obesity. In particular, mouse models are being used to study whether maternal obesity and nutrition before and during pregnancy affect developmental epigenetics in the hypothalamus and, consequently, body weight regulation in the next generation.

Leonard E. Weisman, M.D.

Dr. Weisman's research involves basic, translational, clinical, and epidemiological studies related to neonatal immunity and infection.

Laboratory studies encompass the: development of DNA vaccines for common perinatal pathogens; effects of neonatal neutrophil, immunoglobulin (parenteral, enteral, or transplacental), polyclonal antibody, monoclonal antibody, antibiotic, antibacterial, or immune modulator function on common infectious agents (e.g., Streptococcus, Staphylococcus, Enterococcus, Ureaplasma, respiratory syncytial virus, and fungi) in perinatal animal models. Current clinical studies include: (1) determining if maternal group B streptococcal colonization increases the neonate's risk for early-onset respiratory distress unrelated to infection (epidemiological multi-center), (2) evaluating the effectiveness of antistaphylococcal antibodies (clinical multi-center), (3) staphylococcal infections (epidemiological single-center and multi-center), (4) ureaplasma infection and the development of chronic lung disease (translational, clinical multi-center), (5) ureaplasma infection and the development of preterm labor (translational, epidemiological multi-center), (6) the natural history of ureaplasma colonization/infection in the pregnant woman (epidemiological multi-center, clinical multi-center), (7) neonatal group B streptococcal infection (epidemiological multi-center).

William W. Wong, Ph.D.

Dr. Wong's major research efforts focus on prevention and treatment of childhood obesity and dietary supplementation to prevent chronic diseases.

Currently he is the project director of a community-based childhood obesity intervention program (Healthy Kids-Houston). The after-school program offers nutrition lessons, healthy habits lessons and fun physical activities including aquatic fitness to underserved minority children between 8 and 12 years of age. He is also the senior investigator of a residential summer camp program (Kamp K'aana) designed for obese children between 10 and 14 years of age. The summer camp is designed to promote self-esteem among the obese children and to teach them nutrition and healthy habits to achieve a healthy lifestyle.

Dr. Wong recently completed a, multi-center, randomized, double-blind, placebo-controlled study to document the safety, efficacy, and optimal dosage of soy isoflavones to prevent osteoporosis in postmenopausal womenas well as a NIH-funded project to determine the effects of soy isoflavone supplementation on nitric oxide production, blood pressure, and arterial compliance in postmenopausal women with normal and high-normal blood pressure as well as stage 1 hypertension.

Dr. Wong also is an expert in the use of the doubly labeled water (DLW) method for the estimation of energy expenditure under free-living conditions. Currently, his Gas-Isotope-Ratio Mass Spectrometry Laboratory is the Central DLW Laboratory supporting numerous DLW protocols at Baylor College of Medicine and across the country.

Young Xu, M.D., Ph.D.

My research interests lie in understanding CNS control of body weight, glucose balance and cardiovascular functions.

Homeostatic mechanisms which regulate physiological processes, including feeding behavior, glucose metabolism and blood pressure, are vital to the health of an organism. Disruption of these homeostatic systems can lead to obesity, diabetes and hypertension, disorders that have been major risk factors leading to human mortality. As these conditions have been increasingly prevalent worldwide, it is urgent that we unravel the homeostatic mechanisms controlling energy balance, glycemic control and blood pressure regulation. An ongoing project in the lab is aimed to reveal the CNS mechanisms by which the female sex hormone, estrogen, regulates body weight, glucose homeostasis and blood pressure. The critical approach that makes the cornerstone of my laboratory efforts is the Cre-loxP strategy which allows tissue or cell-specific gene deletion or re-activation in functional mice. This genetic approach is combined with neuroanatomy, systemic physiology and cell-based techniques (1) to genetically dissect the critical neuron populations that respond to estrogen to regulate body weight, glucose and blood pressure, (2) to identify the intracellular pathways in these neurons that mediate estrogen actions, and (3) to unravel the neural circuits downstream of these estrogen-responsive neurons that relay estrogen effects.

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