Faculty Trainers

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).

Rozalyn Anderson, PhD
Assistant Professor of Medicine
Aging Focus Group

RAnderson

Figure 1. “Imaging the Metabolism of Aging” in skeletal muscle from an old rhesus monkey. Different colors of individual fibers reflect cell-type specific differences in metabolism (shades of green). Fibrosis (red strings) and lipofuscin (blue dots) are classic phenotypes of age.

Dr. Anderson studies the biology of aging. Aging is the biggest risk factor for a range of highly prevalent diseases including diabetes, cancer and neurodegenerative disease. The primary goal of Dr. Anderson’s group is to determine the cellular and molecular basis for the age-associated increase in disease vulnerability.  The central theme of this work is age-associated regulation of metabolism and tissue-specificity of the aging response.  One of the ways to learn about aging is through the study of caloric restriction (CR), a dietary intervention that delays aging and the onset of age-associated disease. Our studies in mice and in monkeys point to a key role for metabolism, in particular mitochondrial energy metabolism, in the aging process.  The transcriptional co-activator PGC-1a is a central regulator of energy metabolism. Dr. Anderson has identified a novel mechanism for PGC-1a–directed mitochondrial adaptation that is the focus of her NIH/NIA funded studies. MANTP pre-doc students Karl Miller and Porsha Howell are investigating the factors that regulate PGC-1a at the protein level and how changes in PGC-1a activation and stability influence cellular function in adipocytes.

Alan D. Attie, PhD
Professor of Biochemistry
Metabolic Disease Focus Group

Dr. Attie uses genetic and genomic methods to identify genes  related to obesity-induced diabetes and other metabolic disorders. Two of these  genes that are currently under intense investigation play a role in the  trafficking of insulin containing vesicles in pancreatic b-cells.  The lab uses biochemistry and fluorescence microscopy to study vesicle  trafficking. Other genes under study are regulators of transcription programs  that affect the proliferation and survival of b-cells.  A new project is devoted to discovering genes that determine whether a diabetic  individual will develop nephropathy. Diabetic nephropathy is the leading cause  of kidney failure and a serious and debilitating condition.

AlanImage
Figure 1. The Attie lab studies genes involved in the susceptibility to obesity-induced type 2 diabetes. In one study, they derived a mouse deficient in a gene that they had mapped to a murine type 2 diabetes. In one study, they derived a mous deficient in a gene that they had mapped to a murine type 2 diabetes locus. The electron micrograph shows a striking phenotype caused by the gene deletion. Normal β cells have many dense core vesicle containing insulin. The β cells from the mutant mice are deficient in dense core vesicles and thus, when there is a big demand for insulin as occurs in obesity, they are unable to secrete sufficient insulin to maintain proper glucose levels.

Margaret Clagett-Dame, PhD
Professor of Biochemistry and Pharmacy
Cell Signaling, Growth and Development Focus Group
Fat Soluble Vitamins Focus Group

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. The Clagett-Dame lab uses genetic models to study the function of vitamin A  responsive genes in nervous system development. The mechanism of vitamin  D analog action in the treatment of acne is also under investigation.

John Denu, PhD
Professor of Biomolecular Chemistry
Metabolism and Metabolic Disease Focus Group

DenuDr. Denu’s work focuses in  three areas: Writing, reading  and editing a molecular language/code: What are the basic biochemical principles that govern epigenetic  information written onto histones? Currently, the Denu lab is addressing the  hypothesis that the combinatorial nature of nucleosomal PTM (post-translational  modification, acetylation, phosphorylation, and methylation) states are  specifically recognized and acted upon by enzyme complexes containing  multivalent PTM readers, yielding a histone ‘code’ or ‘language’ that mediates  transcriptional responses. Denu and colleagues empoy biochemical approaches to  investigate the existence of a functional histone code involving  enzyme-catalyzed PTMs. Linking metabolism  with the epigenome: Chromatin remodeling enzymes rely on co-enzymes  derived from metabolic pathways, suggesting coordination between nuclear events  and metabolic networks. Investigations are focusing on the link between  metabolism and the regulation of epigenetic mechanisms. The Denu lab is testing  the hypothesis that certain chromatin modifying complexes have evolved to  exquisitely ‘sense’ metabolite levels and respond accordingly, modifying  specific chromatin loci for altered gene expression. Sirtuins and  reversible protein acetylation: Accumulating evidence suggests that reversible protein-lysine is a major  regulatory mechanism that controls non-histone protein function. Sirtuins are a  conserved family of NAD+-dependent protein deacetylases and  compelling genetic evidence implicates sirtuins in genome maintenance,  metabolism, cell survival, and lifespan. The NAD+-dependence  suggests that specific protein deacetylation is inextricably linked to  metabolism. The Denu lab is testing the  hypothesis that reversible protein acetylation is a major regulatory mechanism  for controlling diverse metabolic processes, and that at the molecular level,  site-specific acetylation alters the intrinsic activity of targeted proteins.

David Eide, PhD
Professor of Nutritional Sciences
Mineral Metabolism Focus Group

EideDr. Eide studies the various mechanisms of metal nutrient uptake and  homeostasis.  He is using the yeast Saccharomyces cerevisiae and human tissue  culture cells as models for understanding these processes in humans and other  organisms. 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 ~80 genes in  response to zinc status and the molecular mechanisms of this regulation are  being determined as are the function of genes regulated by Zap1. Dr. Eide is  also examining the function of mammalian zinc transporters in human cells. His  current focus is on the Zip13 human zinc transporter. Studies to date indicate  that Zip13 is responsible for mobilizing stored zinc from vesicle compartments  of unknown origin. This hypothesis and the identity of these vesicles are being  explored by MANTP postdoctoral trainee Jeeyon Jeong.

Rick Eisenstein, PhD
Professor of Nutritional Sciences
Mineral Metabolism Focus Group

facultytrainers_clip_image002We investigate how erythropoiesis (red cell formation) and iron metabolism are controlled and coordinated including how dysregulation of molecular sensors of iron and oxygen causes disease. Our focus is on iron regulatory proteins (IRP) and the mRNA targets they regulate.  IRP are iron-regulated mRNA binding proteins that dictate the fate of at least 10 mRNA in vertebrates.  Included among these targets is hypoxia inducible factor 2-α (HIF-2α) mRNA which encodes a transcription factor essential for the adaptive response to altered oxygen (e.g. hypoxia) or iron availability. Our current efforts are centered on understanding the mechanistic basis for the dysregulation of erythropoiesis in mice lacking IRP-1  (see below; Hematocrit is a measure of red cell number), the basis for selective translational regulation of HIF-2α mRNA by IRP1 and not IRP2, and the role of multiple RNA elements in controlling the translation of HIF-2α mRNA.  A related project involves genome-wide analysis of the impact of iron and oxygen on translationally regulated mRNAs in mammals. Our work has implications for understanding the underlying mechanisms of, and developing treatments for, diseases caused by insufficient (e.g. nutritional or genetic anemias) or excessive (e.g. polycythemias) production of red blood cells and which impacts the health of millions of people worldwide.  We use a broad array of approaches including biochemical, molecular, genetic and nutritional studies in genetically altered mice, cultured cells and various semi-purified and purified systems using recombinant proteins and wildtype and mutant RNAs.

James Gern, MD
Professor of Pediatrics
Metabolism and Metabolic Disease Focus Group

GernAreas of interest in the Gern laboratory include the biology of rhinoviruses, determining how rhinoviruses contribute to exacerbations of asthma, and relationships between host immune responses, environmental factors, and the development of allergies and asthma. Dr. Gern heads the Urban Environment and Childhood Asthma (“URECA”) study for the Inner City Asthma Consortium.  This is a large observational birth cohort study of children growing up in urban New York, Boston, Baltimore, and St. Louis, and the goal is to identify environmental factors that contribute to asthma.  Dr. Gern also leads a project in the Childhood Origins of Asthma (COAST) birth cohort study to identify how vitamin D status and receptor polymorphisms are related to respiratory illnesses and acute exacerbations of asthma. In addition, the Gern laboratory is working to establish a new birth cohort study to evaluate effects of the farming environment on the development of respiratory illnesses and allergies in young children. Each of these cohort studies provides opportunities to determine how environmental factors and diet affect the development of childhood asthma.

Guy E. Groblewski, PhD
Professor of Nutritional Sciences
Cell Signaling, Growth and Development Focus Group

Guy

Figure 1. Immunofluorescence (left) and corresponding DIC (right) image of D52 in a cluster of pancreatic acinar cells following treatment with the hormone cholecystokinin. D52 is present within an early endosomal compartment in the apical cytoplasm. Astrics denote position of nuclei. Arrows indicate the apical membrane of the cells which is continuous with the pancreatic duct.

Dr. Groblewski studies studies  the molecular control of membrane trafficking events in digestive epithelial  cells using the acinar cell of the exocrine pancreas as a model.  These  studies will define potential targets for therapies against the diseases  pancreatitis pancreatic cancer. Dr. Groblewski’s laboratory discovered a  regulatory molecule called TPD52 that is normally unique to acinar cells yet is  highly expressed in many types of cancer. TPD52 regulates endosomal membrane  trafficking and epithelial differentiation. Additionally, he has established  functional roles for SNARE proteins, small Rab G-proteins and inositol  phospholipids in controlling acinar cell secretory function.  New evidence  indicates that genetic manipulation of these regulatory molecules in rodents and  isolated cells strongly impacts the onset and progression of pancreatitis which  if left unchecked leads to pancreatic cancer.

Karen Hansen, MD
Associate Professor of Medicine
Mineral Metabolism Focus Group

HansenReduced calcium absorption is a risk factor for osteoporosis. The Hansen team focuses on factors influencing calcium absorption, using a gold-standard approach comprised of dual stable calcium isotopes, and a 24-hour inpatient admission to collect urine and measure isotope concentrations, and replication of typical dietary intake during the 24-hour stay based on analysis of outpatient diet records. Prior studies evaluated the change in calcium absorption with correction of vitamin D insufficiency, use of proton pump inhibitors and use of aromatase inhibitors. A large ongoing double-blind placebo-controlled trial hopes to clarify whether one year of high-dose vitamin D is superior to low-dose vitamin D in postmenopausal women with initial vitamin D insufficiency; study outcomes include changes in calcium absorption, bone mineral density and muscle fitness. Future studies look to clarify the benefits of bio-active vitamin D therapy for patients with chronic kidney disease.

Kenneth Kudsk, PhD
Professor of Surgery
Cell Signaling, Growth and Development Focus Group

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Figure 1. Gut associated lymphoid tissue and mucosal immunity.

Dr. Kudsk investigates the immunologic and physiologic influences of route of nutrient administration on the gastrointestinal tract and upper and lower respiratory tracts. The laboratory has focuses on both acquired and innate mucosal immunity, the intestinal and systemic inflammatory responses, and antibacterial and antiviral defenses after nutrient manipulation. In addition, several clinical trials have correlated the laboratory finding s discovered in the mouse model with clinical responses in critically injured, ICU patients. Trainees participate in all aspects of these studies.

Huichuan Lai, PhD
Professor of Nutritional Sciences
Metabolism and Metabolic Disease Focus Group

LaiDr. 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-shortening genetic disorders. The ultimate goal of the CF research is to develop evidence-based clinical practice guidelines for improving clinical care and outcomes of patients with CF.  Current CF projects include: 1) develop novel nutrition indicators and risk models predictive of genotype-phenotype associations, 2) evaluate effectiveness of the Wisconsin CF Newborn Screening Program, and 3) investigate the benefits and risks of breastfeeding on clinical outcomes of CF infants through a multi-center study (Madison, Milwaukee, Boston, Indianapolis and Salt Lake City). Answering the breastfeeding question is particularly urgent as the entire US implemented newborn screening for CF in 2010 but optimal feeding for CF infants is unknown. Dr. Lai’s asthma and obesity research uses one of the 5 large birth cohorts established in the US to investigate the hypothesis that diet is a common risk factor for childhood obesity and asthma. Trainees conduct human clinical studies and advanced statistical analyses.

Julie Mares, PhD
Professor of Ophthalmology and Visual Sciences
Fat Soluble Vitamins Focus Group

Mares

Figure 1. Relationship between macular pigment optical density (MPOD), dietary intake of lutein and zeaxanthin and signal nucleotide polymorphisms in the carotenoid cleavage enzyme (BCMO1) gene. Meyers K., et al Invest Ophthalmol Vis Sci. (2013) 54:2333-45

The primary goal of Dr. Mares’s research program is to evaluate relationships of diet and nutritional status to eye and brain health. This includes the study of the onset and progression of diseases that become common in old age such as cataract, glaucoma and macular degeneration. They conduct studies in several large population groups using epidemiological approaches.      The Mares group evaluates many interrelated aspects of diet and healthy lifestyles singly and jointly. In some studies, we use a non-invasive flicker photometry test to evaluate levels of plant pigments (the carotenoids lutein and zeaxanthin) that accumulate in eye tissues and comprise macular pigment. We measure blood levels of vitamin D which reflect vitamin D from both diet and sunlight exposure.     They are currently studying genetic predictors of the status of carotenoids that accumulate in the eye and genetic predictors of vitamin D status. We will next use these findings to study how nutritional and genetic factors are jointly related to lower risk for developing age-related deterioration of eye and brain health in different study populations. Ultimately these data will be used to understand and communicate modifiable aspects of diet and lifestyle that could promote eye and brain health as we age.

Denise M. Ney, PhD
Professor of Nutritional Sciences
Metabolism and Metabolic Disease Focus Group

Dr. Ney studies the nutritional management of phenylketonuria (PKU) by conducting studies in human PKU (www.clinicaltrials.gov NCT 01428258) and the murine model of PKU (Pahenu2).  PKU is caused by a deficiency of hepatic phenylalanine hydroxylase (PAH, EC 1.14.16.1) activity that catalyzes the conversion of phenylalanine (phe) to tyrosine. With normal protein intake, phe accumulates in the brain leading to profound cognitive impairment.  A lifelong low-phe diet that includes amino acid formula is required to protect brain development. Dr. Ney has developed a more physiologic approach for the nutritional management of PKU using glycomacropeptide (GMP), a low-phe protein isolated from cheese whey. Skeletal fragility, characterized by low bone mineral density and fractures, is a chronic complication of PKU of unknown etiology. Skeletal fragility in murine PKU is attenuated with the GMP diet, compared with an amino acid diet.  Studies are underway to characterize the pathophysiology of skeletal fragility in human and murine PKU.

Figure 1. Phenylalanine (phe) metabolism in phenylketonuria (PKU). As indicated by the “X”, PKU results from mutations (over 800 have been identified) that affect the hepatic phe hydroxylase (PAH) enzyme needed for the hydroxylation of the indispensable amino acid phe to tyrosine. PKU may also result from mutations in the recycling of the essential PAH cofactor tetrahydrobiopterin. Due to these mutations which reduce the conversion of phe to tyrosine, phe accumulates in blood and is transaminated and decarboxylated into many compounds which appear in blood and urine; three of the compounds which are measured clinically are shown. Tyrosine, a precursor for multiple biological products, becomes an indispensable AA and must be provided by the diet for those with PKU. Under physiological conditions PAH catalyzes about 75% of the phe input from the diet and protein catabolism.

Figure 1. Phenylalanine (phe) metabolism in phenylketonuria (PKU). As indicated by the “X”, PKU results from mutations (over 800 have been identified) that affect the hepatic phe hydroxylase (PAH) enzyme needed for the hydroxylation of the indispensable amino acid phe to tyrosine. PKU may also result from mutations in the recycling of the essential PAH cofactor tetrahydrobiopterin. Due to these mutations which reduce the conversion of phe to tyrosine, phe accumulates in blood and is transaminated and decarboxylated into many compounds which appear in blood and urine; three of the compounds which are measured clinically are shown. Tyrosine, a precursor for multiple biological products, becomes an indispensable AA and must be provided by the diet for those with PKU. Under physiological conditions PAH catalyzes about 75% of the phe input from the diet and protein catabolism.

Peter Nichol MD, PhD
Associate Professor of Surgery
Cell Signaling, Growth and Development

Figure 1. The intestinal recovery response. Following mutation of Fgfr2IIIb, endodermal cells (pink) undergo apoptosis (A and B). (C) Mesodermal cells are activated (yellow green) and invade (D) the endoderm compartment. Following invasion, the mesodermal cells (pink round) undergo lineage reprogrammed (D and E) and assume to an endodermal fate enabling recovery to occur and development to resume.

The Nichol laboratory studies how the  intestinal mucosal cells respond to injury in order to understand the  fundamental processes critical for intestinal repair. The intestinal  mucosa is an endoderm derived layer of tissue that lines the intestinal lumen  and to throughout life performs the essential function of nutrient absorption.  The majority of non-cancerous intestinal diseases arise from injury to the  intestinal mucosa. Restitution and repair of this layer of tissue is  incompletely understood.. The Nichol laboratory uses a well-established genetic  mouse model of intestinal atresia; a birth defect in which a portion of the intestine is absent resulting  in a loss  of continuity of part of the intestinal tube. Using this model they  have observed that cells originating from lineages outside the intestinal  endoderm invade and re-populate the endodermal compartment following the  massive loss of the endoderm lineage through apoptosis. These invading cells  then go on to express endodermal markers and intestinal development resumes in  seemingly normal fashion. These data  indicate a previously unknown capacity  of the embryonic small intestine to recover from a massive loss of endodermal  cells.  The Nichol laboratory focuses on  this process of endoderm recovery, signals stimulating it and the lineage  reassignment of non-endodermal cells to an endodermal fate.

James Ntambi, PhD
Professor of Biochemistry and Nutritional Sciences
Metabolism and Metabolic Disease Focus Group

Dr. Ntambi studies how fat metabolism impacts obesity and obesity-related  diseases.   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  predoctoral trainee Maggie Strable and former postdoctoral trainee Matt Flowers  have shown that hepatic SCD1 is of central importance for conversion of dietary  carbohydrates to fatty acids in high-carbohydrate diet feeding, but skin is  important for resistance to high-fat diet-induced phenotypes associated with  global loss of SCD1 function.  Recently Maggie Strable has generated  transgenic mouse SCD models to study the differential metabolic effects of  hepatic monounsaturated fatty acids. These and related studies will determine  the substrate specificities of the various SCD isoforms and overall  contribution of hepatic  de novo lipogenesis and skin derived factors in the regulation of metabolism.

David Pagliarini, PhD
Associate Professor Biochemistry
Metabolism and Metabolic Disease Focus Group
Mineral Metabolism Focus Group

PagliariniDr. Pagliarini studies  mitochondria — complex organelles whose dysfunction underlies a broad  spectrum of human diseases. Mitochondria house a wide range of metabolic  pathways, and are central to apoptosis, ion homeostasis and reactive  oxygen species production. Thus, to maintain cellular homeostasis cells  must exert careful control over their mitochondrial composition and  function. How do cells custom-build mitochondria to suit their  metabolic needs? What mechanisms do cells leverage to efficiently control  mitochondrial processes? Which mitochondrial processes are disrupted  in diseases and how might these be targeted therapeutically?  The Pagliarini lab takes a multi-disciplinary approach to  investigating these questions. By integrating classic biochemistry,  molecular biology and genetics with large-scale proteomics and  systems approaches, we aim to elucidate how cells regulate mitochondrial  metabolism and establish a customized mitochondrial infrastructure  across tissues and in response to a changing cellular environment.

Tomas Prolla, PhD
Professor of Genetics
Aging Focus Group

untitledDr. Prolla is focused on understanding the molecular basis of  the aging process and its retardation by caloric restriction. Our  studies have uncovered a central role for mitochondria and energy metabolism in  both aging and its retardation by caloric restriction. We use  the mouse as model system and most of our studies are based on the construction  of mouse models of accelerated or retarded aging. The Prolla lab generated  these models through the use of gene targeting in ES cells, as well as  transgenic animal construction. An example of such work from the Prolla  laboratory is a widely used model of age-related mitochondrial dysfunction,  mice deficient in the exonuclease domain of the mitochondrial  DNA polymerase gamma (PolgD257A).  They have previously used DNA microarrays to  shown that caloric restriction leads to a “metabolic reprogramming” at the  transcriptional level. Their more recent studies have focused on the role of  the sirtuin SIRT3 in mediating the beneficial effects of caloric restriction in  aging, including such metabolic reprogramming. SIRT3 is a NAD+ dependent  deacetylase located in the mitochondrial matrix that induces metabolic shifts  in response to caloric restriction. Such metabolic shifts appear to increase  oxidative stress resistance and prevent an increase in age-related apoptosis.  They are investigating if this metabolic adaptation underlies the beneficial effects  of caloric restriction in age-related diseases (e.g. age-related hearing loss  (AHL)) as well as age-related physiological declines.  The long-term goal of our studies is to  identify critical pathways in aging and find either natural or synthetic compounds  that modulate such pathways in a favorable manner.

Sherry Tanumihardjo, PhD
Professor of Nutritional Sciences
Fat Soluble Vitamins Focus Group

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. The Tanumihardjo laboratory 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 developed a stable isotope method  that is very sensitive and provides enhanced accuracy over prior methods, which  has been to determine human vitamin A requirements. Her carotenoid studies have  examined the uptake and clearance of carotenoids from specialty carrots and  staple crops through chronic and acute feeding.

C.-L. Eric Yen, PhD,
Associate Professor of Nutritional Sciences
Metabolism and Metabolic Disease Focus Group

YenDr. Yen studies studies mechanisms by which enzymes involved in  triacylglycerol synthesis modulate systemic responses to diets. Dr. Yen’s group  uses genetically engineered mice as models to examine the physiological roles  of these enzymes, especially those involved in the regulation of energy  balance. One current focus is on MGAT2, which mediates fat absorption in the  small intestine. Mice lacking the enzyme are protected against obesity and  other metabolic disorders normally induced by high-fat feeding. Interestingly, they  absorb normal quantity of dietary fat but exhibit increases in energy  expenditure. The Yen group is investigating how MGAT2-mediated intestinal lipid  metabolism regulates gut hormone secretion, systemic substrate partitioning,  and gut microbiota.