MANTP

The MANTP is composed of 18 faculty researchers from seven departments in either the College of Agricultural and Life Sciences (CALS) or the School of Medicine and Public Health (SMPH).

Alexandra Adams, MD, PhD
Assistant Professor of Family Medicine

Dr. Adams studies obesity and cardiovascular disease prevention working with Wisconsin Native American tribes.  Projects include a randomized intervention study of home-visitation to support healthy lifestyle behavior changes in families with children ages 3-5.  A supportive communities approach is also used to address environmental barriers and supports to healthy lifestyles.  A participatory research process is being used throughout all phases so that community and academic researchers work together on data collection, analysis and intervention design.  Dr. Adams postulates that prevention strategies designed in partnership with the community have the best chance for success.  Undergraduate and medical students provide data collection and entry, data analysis and design of intervention materials.  Postdoctoral researchers contribute intervention and curricula design, data analysis and interpretation.  Dr. Adams has collaborates with MANTP trainer Dr. Schoeller.

Alan D. Attie, PhD
Professor of Biochemistry

Dr. Attie studies the genetics and genomics of type 2 diabetes.  Type 2 diabetes involves an impaired response to insulin and the failure of pancreatic ß-cells to compensate with sufficient insulin release to properly moderate blood glucose.  Diet and obesity collaborate with genetics to produce diabetes.  Dr. Attie’s group has created a mouse model for identifying genes that influence whether obesity will result in diabetes. Through a genome-wide mapping study, they have mapped several gene loci that contribute to diabetes and to obesity.  Dr. Attie is using these genetic effects to reveal new biochemical mechanisms underlying the key features of diabetes.  A former MANTP predoctoral trainee, Jessica (Byers) Flowers, was involved in the positional cloning of the relevant gene loci and conducted critical biochemical studies to elucidate the molecular basis of insulin resistance and ß-cell failure.  Dr. Attie collaborates extensively with MANTP trainer Dr. Ntambi.

Paul Bertics, PhD
Professor of Biomolecular Chemistry

Dr. Bertics focuses on the relationship between epidermal growth factor (EGF) and bacterial toxin (lipopolysaccharide or LPS)- and cytokine-initiated cell signaling in normal and disease states such as cancer and certain inflammatory disorders.  One focus related to trainee training involves a delineation of the determinants involved in specifying and regulating the substrate specificity, catalytic capacity and general function of the EGF receptor protein-tyrosine kinase.  The EGF receptor is important in cell growth control, and its inappropriate activation has been linked to the development of many human cancers.  A second focus of research entails the analysis of cytokine/toxin signaling in immune cells, including monocytes, macrophages and eosinophils. Using LPS as a convenient tool for understanding the macrophage activation process has helped identify important elements in the signal transduction pathways and may lead to the development of new therapeutics for multiple diseases including those with a major nutrition component (e.g. Crohn’s disease).

Margaret Clagett-Dame, PhD
Professor of Biochemistry

Dr. Clagett-Dame studies the mechanism of action of the fat-soluble vitamins A and D and the therapeutic applications of vitamin analogs.   The active forms of vitamin A and D, all-trans retinoic acid (atRA) and 1,25-dihydroxycholecalciferol, act by binding to nuclear receptor proteins that function as ligand-activated transcription factors and modulate gene expression.  Vitamin A is important in regulating cellular growth and differentiation.  Embryonic development is disrupted both in vitamin A deficiency and excess.  The Clagett-Dame lab has developed nutritional models to study the function of vitamin A in both early and late developmental processes.  Using molecular cloning approaches, the lab has identified a number of novel atRA-responsive genes that are highly expressed in the nervous tissues of developing embryos.  MANTP predoctoral trainee, Elizabeth McNeill, is currently studying the function of one of these, Nav2, in neurite outgrowth and embryonic development.  Retinoids and vitamin D analogs with therapeutic potential for the treatment of osteoporosis, adipocyte differentiation, and acne are also under investigation.

Marc Drezner, MD
Professor of Medicine

Dr. Drezner studies the molecular mechanisms of phosphate homeostasis in humans and the influence of Vitamin D and bone mineralization on these mechanisms.  The Drezner group has used mouse models of human diseases to provide new insights.  For example, they recently identified gene, PHEX, that is responsible for X-linked hypophosphatemia.  The mechanism(s) linking PHEX with hypophosphatemia, renal phosphate wasting, abnormal Vitamin D metabolism, and bone mineralization defects are now under investigation.  Trainees participate in all aspects of these studies.  For example, postdoctoral trainees in the lab are investigating the phenotypic abnormalities of phex-/- mice and aberrant bone remodeling processes mediated by osteoblasts and osteoclasts.  In other studies, the dissociation between mRNA levels and activity of 25(OH)-1a-hydroxylase activity is being examined.  The Drezner lab is also investigating the mechanisms underlying the abnormal renal phosphate transport and the resulting hypophosphatemia in phex-/- mutant mice.

David Eide, PhD
Professor of Nutritional Sciences

Dr. Eide studies the mechanism of metal nutrient uptake and homeostasis.  He is using the yeast Saccharomyces cerevisiae as a model for understanding these processes in humans.  Dr. Eide has shown that zinc homeostasis in yeast is regulated through both transcriptional and post-translational mechanisms.  At the transcriptional level, the Zap1 transcription factor controls ~60 genes in response to zinc status and the molecular mechanisms of this regulation are being determined.  Zap1 has two activation domains that are independently regulated by zinc and the project of one MANTP predoctoral trainee, Avery Frey, is to determine the unique roles of these two domains in zinc homeostasis.  Dr. Eide's studies have also shown that zinc controls the subcellular localization and stability of zinc transporters involved in zinc uptake and intracellular sequestration of zinc.  MANTP postdoctoral trainee Charissa Ellis is studying the post-translational regulation of zinc transporters in the secretory pathway.

Richard S. Eisenstein, PhD
Professor of Nutritional Sciences

Dr. Eisenstein studies how iron regulatory proteins (IRPs) maintain iron homeostasis in mammals.  IRPs bind to sites (IREs) in the untranslated regions of target mRNA and modulate mRNA translation or stability.  Iron regulates IRP1’s IRE binding by inducing formation of an Fe-S cluster in IRP1 converting it to the cytosolic isoform of aconitase.  Former MANTP trainees Joe Pitula and Stephen Clarke studied how phosphorylation alters IRP1 function.  Pitula found that Ser 711 phosphorylation of IRP1 had unexpected effects on its aconitase function without altering RNA binding suggesting new mechanisms to control citrate metabolism.  Clarke showed that IRP1 Ser 138 phosphorylation invoked a novel mechanism for iron regulation of IRP1 activity.  He showed that IRP1 function was controlled by a compensatory protein degradation mechanism when Fe-S assembly was disrupted.  These studies have implications for the regulation of iron metabolism during cell proliferation, inflammation and in diseases altering Fe-S cluster assembly/disassembly. 

Guy E. Groblewski, PhD
Associate Professor of Nutritional Sciences

Dr. Groblewski studies how diet regulates digestive epithelial cell function by identifying the regulatory molecules that influence nutrient transport and protein secretion.  These studies will define potential targets for therapies against numerous disorders including nutrient deficiencies caused by impaired GI function, pancreatitis, and cancer.  Dr. Groblewski's laboratory is one of the few in the world working on a family of molecules called TPD52 proteins that are involved in membrane trafficking and cell proliferation.  He has established a functional role for one of these proteins, CRHSP-28, in the Ca2+-regulated secretory pathway of pancreatic acinar cells.  A previous PhD student, Kala Kaspar, defined the Ca2+-dependent phosphorylation of CRHSP-28.  A second project focuses on heat shock protein 70 (HSP70) and its co-chaperone, CSP.  MANTP predoctoral trainee Megan Baumler is determining the role of these proteins in preventing acute pancreatitis.  Dr. Groblewski has collaborated with MANTP trainer Dr. Ney.

Joseph Kemnitz, PhD
Professor of Physiology

Dr. Kemnitz studies neurobehavioral and hormonal mechanisms that control food intake and energy expenditure and the consequences of caloric imbalances.  His projects utilize rhesus monkeys as a primate model for humans and recent efforts have focused on changes that occur in middle and late life. These projects include evaluations of metabolic rate in obese and lean monkeys and studies of how certain hormones may act on the hypothalamus to modulate food intake and energy expenditure.  The relationship between energy balance and the processes of aging is also being assessed prospectively in a multidisciplinary study of rhesus monkeys.  Effects of reduced food intake in these primates are consistent with the retardation of disease and extension of lifespan that has been demonstrated for food restricted non-primate species.  Dr. Kemnitz collaborates with MANTP trainers Dr. Schoeller and Dr. Weindruch.   

HuiChuan Lai, PhD
Assistant Professor of Nutritional Sciences

Dr. Lai studies how nutrition affects the onset and progression of pediatric chronic diseases. This research includes cystic fibrosis (CF), asthma, and obesity. CF is one of the most common life-threatening genetic disorders.  Dr. Lai’s research uses population databases to develop risk models that predict the relationships among malnutrition, pulmonary decline, quality of life and survival. The ultimate goal is to improve the diagnosis, treatment and health outcomes for CF patients. Her asthma and obesity research focuses on investigating the hypothesis that diet is a common risk factor for childhood obesity and asthma, and that the occurrence of obesity and asthma are related. Previous studies in this area were hampered by the lack of prospective cohorts followed from birth and validated methods for collecting relevant data.  Dr. Lai’s  Diet-Asthma-Obesity project uses one of the 5 large birth cohort studies established in the US to investigate this hypothesis. Trainees conduct human clinical studies and advanced statistical analyses.

Denise M. Ney, PhD
Professor of Nutritional Sciences

Dr. Ney studies the neuroendocrine regulation of intestinal adaptation.  Massive resection of the intestine reduces absorptive surface area leading to a complex of symptoms termed “short bowel syndrome.”  Intestinal adaptation following bowel resection is a poorly understood.  Their goal is to test the hypothesis that intestinal adaptation is regulated by a neuroendocrine pathway including the vagal nerve and intestinal growth factors, glucagon-like peptide-2 (GLP-2) and insulin-like growth factor-I (IGF-I).  Results from former MANTP predoctoral trainee David Nelson’s researcher indicated that vagal afferent innervation is essential for maximal resection-induced intestinal adaptive growth through a mechanism that involves stimulation by luminal nutrients.  Moreover, we demonstrated that the GLP-2 receptor is present on vagal afferents and is functional based on activation of the brainstem after interperitoneal injection of GLP-2.  Recent evidence suggests that IGF-I is a downstream mediator of GLP-2 action.  Experiments in genetic mouse models are planned to test the role of IGF-I in GLP-2 mediated intestinal growth.  

James M. Ntambi, PhD
Professor of Biochemistry and Nutritional Sciences

Dr. Ntambi studies how fat metabolism impacts obesity and obesity-related diseases.  He is also studying the genetics of obesity in close collaboration with Dr. Attie, a fellow MANTP trainer.   Dr. Ntambi is using animal models to understand the regulation of carbohydrate and lipid metabolism.  His research focuses on liver, muscle, adipose tissue, brain and kidney and with the ultimate goal of preventing and treating human disorders. Current studies examine the regulation of the stearoyl-CoA desaturase (SCD) gene expression during fat cell differentiation and its role in lipid and carbohydrate metabolism.  Dr. Ntambi’s laboratory also studies the function and regulation of the various SCD genes and their role in leptin signaling in the CNS and in peripheral tissues.  For example, using a liver-specific SCD1 knockout mouse, MANTP postdoctoral trainee Matt Flowers has shown that hepatic SCD1 is of central importance for conversion of dietary carbohydrates to fatty acids in high-carbohydrate diet feeding, but other tissues are more important for resistance to high-fat diet-induced phenotypes associated with global loss of SCD1 function.  These and related studies will determine the substrate specificities of the various SCD isoforms and their overall contribution in metabolism.  The Ntambi lab collaborates with MANTP trainer Dr. Attie.

Tomas Prolla, PhD
Professor of Genetics

Dr. Prolla studies aging and its retardation through caloric restriction (CR).  He has used microarrays to obtain a genome-wide expression profile of the aging process.  Dr. Prolla's studies represent some of the first in the new field of nutritional genomics.  His studies have revealed that aging is associated with the induction of gene families involved in oxidative stress, inflammation, and processing of misfolded proteins, and the down-regulation of genes involved in energy metabolism.  In contrast, studies of CR mice suggest that aging is retarded through a metabolic shift associated with profound transcriptional reprogramming.  He is currently extending these studies to multiple tissues of mice and rhesus monkeys in collaboration with MANTP trainer Richard Weindruch.  Prolla lab trainees are complementing these studies with the generation of transgenic and "knock-out" mice that overexpress or are deficient in specific genes, and analyzing the influence of these interventions on the aging process.  Thus, these studies will uncover genetic pathways that control longevity in mammals.

Dale A. Schoeller, PhD
Professor of Nutritional Sciences

Dr. Schoeller studies energy metabolism in humans using stable isotope techniques for analysis of energy expenditure, macronutrient oxidation, and body composition.  The primary focus is assessing the role of physical activity in weight control.  Dr. Schoeller demonstrated that physical exercise protects previously obese women from weight regain.  He and his students have determined that this protection involves an up-regulation of dietary fat oxidation.  Using stable isotopic tracers, they showed that exercise increased dietary oleate, but not palmitate, oxidation.  MANTP predoctoral trainee Jamie Cooper is testing the hypothesis that the time required to increase fat oxidation to match fat intake on a high-fat diet will be shorter for monounsaturated fats compared to saturated fats and fat oxidation will be enhanced with exercise.  Additional studies will investigate whether exercise interventions also alter circulating hunger and satiety factors and thus feeds back to appetite and energy balance.  A second research focus is on the beneficial effects of caloric restriction (CR) on longevity and health status working with MANTP trainers Dr. Weindruch and Dr. Kemnitz.

Susan Smith, PhD
Professor of Nutritional Sciences

Dr. Smith investigates how dietary agents affect the risk of birth defects.  Her overall goal is to identify an agent’s underlying mechanism of action drawing upon fundamental understanding of morphogenesis and development.  Much of her work considers two agents, vitamin A (retinoids) and alcohol focusing on two organs, the neural crest of the early nervous system, and the developing heart.  Trainees incorporate the advances in developmental biology to establish the molecular mechanisms by which such agents affect the embryo and how they produce or prevent a risk for congenital defects.  Trainees address these questions using diverse animal models, including transgenic mice, in ovo chick, and dietary-manipulated rats and mice.  For example, predoctoral trainee Echo Rufer investigates the role of iron status in affecting fetal alcohol syndrome risk in the offspring.  Echo developed a rat model of mild maternal iron inadequacy, and then challenges the offspring with ethanol to target the developing cerebellum and hippocampus.  She then evaluates brain histology and behavioral learning in the adolescent rats after alcohol challenge.

Roger A. Sunde, PhD
Professor of Nutritional Sciences

Dr. Sunde studies molecular selenium (Se) nutrition, including Se deficiency and excess, to understand nutrient regulation of gene expression, the molecular mechanisms of Se regulation, and the biological functions of Se.  In lay terms, he is characterizing the molecular thermostats that control cellular Se status and using this to determine requirements.  The two major projects in his lab are 1) to develop molecular biology-based assays for assessment of human Se status, and 2) to define mechanisms involved in regulating Se homoeostasis at the level of retention and excretion.  Kim Hargrave, a current MANTP postdoctoral trainee, recently completed a microarray study in mice to characterize regulation of all known selenoproteins.  These data will be used in the development of new assays for Se status assessment.  In addition, over 100 new genes were identified that are specifically regulated by Se.  This latter group represents good candidates for genes involved in Se homeostasis.  Anna Rothert, a predoctoral student, is using the nematode C. elegans to test the function of orthologs of these mouse genes in a genetically tractable system.

Sherry A. Tanumihardjo, PhD
Associate Professor of Nutritional Sciences

Dr. Tanumihardjo has two major research foci: methods of vitamin A assessment and carotenoid bioavailability.  Special emphasis is on provitamin A in staple crops to improve vitamin A status in humans world-wide.  Dr. Tanumihardjo is developing new techniques to assess vitamin A status.  She uses several animal models to develop and test hypotheses, i.e., rats, gerbils, pigs, and monkeys.  Ultimately, her methods are applied to humans for evaluation.  Her trainees have developed and simplified methods, e.g. the modified relative dose response test and breast milk retinol determinations, which can be used in labs lacking sophisticated equipment.  Dr. Tanumihardjo has also developed a stable isotope method that is very sensitive and provides enhanced accuracy over prior methods.  Ultimately, she plans to use stable 13C methods to determine human vitamin A requirements throughout the life cycle.  Her carotenoid studies have examined the uptake and clearance of carotenoids from specialty carrots and staple crops through chronic feeding. 

Richard Weindruch, PhD
Professor of Medicine

Dr. Weindruch is exploring the caloric restriction (CR) paradigm in collaboration with MANTP trainers Schoeller, Prolla and Kemnitz.  Of the many interventions tested to slow the aging process in homeothermic vertebrates, only CR has proven to be highly effective.  CR involves the reduction of calorie intake but without deficiencies in other essential nutrients.  Dr. Weindruch is testing the hypothesis that a fundamental way by which CR retards aging is by reducing oxidative stress.  A particular focus is on mitochondrial metabolism as this organelle may be involved in producing reactive metabolites involved in aging and age-associated diseases.  Weindruch’s studies revealed that antioxidants vitamins C and E are not as effective as CR in extending the life span in rodent models.  Instead, using microarrays, he found that CR slows aging through reduction of free radical damage to tissues as seen by increased expression of enzymes involved in antioxidant defense and related pathways.  As a step towards assessing the role of CR in human aging, Dr. Weindruch also studies the possibility that CR may retard the rate of aging in rhesus monkeys. He collaborates with MANTP Trainers Dr. Prolla, Dr. Schoeller and Dr. Kemnitz.