| The research interests of the training faculty are described in more detail in the paragraphs that follow. Postdoctoral trainees can 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 suggest a discrete portion of a larger project that the trainee can pursue as his/her research project.
Dr. Abrams conducts studies of iron
and zinc bioavailability in children including children
in developing countries. These studies are performed
to evaluate the sources of these key minerals and to
identify interactions between them. Study populations
of interest include children and adults of all ages,
from premature infants to elderly women with osteoporosis.
Studies are performed by administering stable minor
isotopes of the elements of interest and following
the time course of the isotopes in blood, urine, and
stool. Intravenously administered isotopes are used
to assess the rate of bone mineral deposition and the
secretion of minerals into the gastrointestinal tract.
Numerous models of calcium and magnesium kinetics are
used to evaluate bone mineralization and resorption
processes. The principal analytical tool utilized is
a thermal ionization mass spectrometer, a state-of-the-art
device capable of highly precise measurements of isotopes
isolated from biological samples and one of only a
few such instruments available for nutrition research.
Current studies focus specifically on growing infants
and children in an attempt to evaluate dietary recommendations
for intake of calcium, magnesium, zinc and iron.
Dr. Baranowski and his team have developed, implemented
and evaluated school and community-based interventions
for enabling students and their families to eat more
fruit and vegetables and to be more physically active
as obesity preventive and chronic disease protective
lifestyle behaviors. The interventions are based on
social cognitive theory and employ one or more of classroom
curricula, newsletters for parents (with joint parent-child
home activities), home videos, point-of-purchase education,
classroom interactive multimedia educational games,
summer day camps, internet-based programs for girls
and their parents, troop meetings, camping and internet
based activities for Boy Scouts and changes in school
food services. The team collaborated on a project to
use the school as a channel to change the diet of African-American
parents of fourth graders and has recently been funded
to design, implement and evaluate a middle school diabetes
prevention program as part of a multi-site behavioral
trial. Smaller projects investigate the role of goal
setting and problem solving processes in children's
dietary and physical activity practices, the influences
on home fruit, juice and vegetable availability, and
the mechanisms by which families influence children's
physical activity.
Dr. Bier's primary research interest is the regulation
of interorgan transport of metabolic fuels. This interest
encompasses the substrate and hormone regulation of
glucose, lipid and protein/amino acid fuels. Under
this rubric, his work has extended in two principal
directions. The first entails regulation of endogenous
fuel availability for metabolic functions when a subject
is ill and incapable of ingesting adequate quantities
of food. The second involves assessment of the metabolic
fates of ingested exogenous fuels under various classical
nutritional circumstances. Research employs a wide
variety of stable-isotope tracer kinetic methods to
quantify substrate flux, metabolism, precursor-product
relationships, and irreversible oxidation of excreted
end products. The physiological information thus obtained
has also been used to further assess aberrations in
interogran fuel transport consequent to a wide variety
of pathological conditions. Dr. Bier's work has provided
data on the physiologic and pathophysiologic regulation
of metabolic fuel transport of body protein, fat and
carbohydrate in a wide variety of circumstances spanning
a spectrum of ages from extreme prematurity to the
elderly.
The objective of Dr. Burrin's research is to elucidate
the cellular and hormonal signals that mediate the
stimulatory effects of enteral nutrition on the growth
and function of the neonatal intestine. Previous studies
have shown that macronutrients produce a greater trophic
stimulus in the neonatal intestine than growth factors
such as IGF-I ingested in breast milk. Current studies
focus on establishing the optimum quantity and composition
of enteral nutrients necessary to maintain normal intestinal
growth and function.
Additional studies investigate the physiological
significance of the gut-derived peptide, glucagon-like
peptide-2 (GLP-2), and how it impacts intestinal protein
and amino acid metabolism in the neonatal pig. The
studies utilize isotopic tracers coupled with arteriovenous
organ balance measurements to quantify the intestinal
absorption and metabolism of macronutrients provided
either enterally or parenterally. Using this approach,
he plans to determine how the catabolic effects of
dexamethasone compromise intestinal absorptive function
and how provision of either minimal enteral nutrition
or GLP-2 ameliorates the actions of dexamethasone.
These studies also will determine how these nutritional
and hormonal factors modulate rates of cellular protein
turnover, proliferation and programmed cell death.
How these factors affect the expression and activity
of key intermediates in these cellular pathways also
will be investigated.
The overall goal of Dr. Butte's
current research is to identify environmental and genetic
determinants of childhood obesity in "at risk" children.
To do so, 500 obese Hispanic children and their biological
parents and siblings will be identified and phenotyped.
In addition, a systematic genomic scan will be performed
to localize quantitative trait loci that influence
quantitative variation in body composition, energy
expenditure, physical activity, food intake and/or
eating behavior.
Dr. Butte's previous research has played a major
role in defining energy requirements of pregnant and
lactating women and their infants with respect to pregnancy
outcome, lactation performance as well as infant growth
and development. The mechanisms underlying energy adaptations
during pregnancy, lactation and infancy are now under
investigation. To achieve these research goals, methodologies
have been developed to measure energy expenditure and
body composition in the populations of interest; these
include room and portable respiration calorimeters
for use in adults and infants, the doubly labeled water
method for the measurement of free-living total energy
expenditure and several devices for measuring body
composition.
Dr. Chan's major research area concerns
the molecular regulation of lipid homeostasis. Over
the last twenty years, his laboratory has applied molecular
biology techniques to the structure and regulation
of various genes related to lipid homeostasis, including
the genes for the major apolipoproteins and lipolytic
enzymes. The effects of lipid nutrients on the expression
of these genes have also been a major focus. Current
projects concern the interaction of various lipid-modifying
genes on plasma lipoprotein metabolism and on atherogenesis
in transgenic mouse models. His trainees have created
gene knockout mice that produce only apoB-100 but no
apoB-48. His laboratory is now studying the apoB-100
only animals in the presence and absence of cholesteryl
ester transfer protein (CETP), apoE, and LDL receptor
expression. Other areas currently under exploration
concern the role of adipocyte-specific gene expression
on obesity and weight control and the mechanism of
the abnormal lipid metabolism in diabetic animal models.
Dr. Cullen's research focuses on
the prevention of diet-related chronic diseases through
the development, implementation, and evaluation of
nutrition behavior change programs for children and
adolescents. Of particular interest are programs utilizing
unique delivery channels to improve children's fruit
and vegetable consumption. Current projects include
implementing and evaluating an environmental behavior
change program for middle school cafeterias and a
la carte snack bars that includes social marketing
within the cafeteria environment, developing and implementing
a school-based program for the prevention of type 2
diabetes among youth, and a feasibility study of an
internet-based dietary behavior change program for
African-American families.
Dr. Davis' research focuses on identifying the mechanisms
by which nutrients, hormones, and growth factors regulate
protein deposition during growth and development, particularly
in skeletal muscle. Early studies demonstrated that
the high rate of protein deposition in the neonate
is due to the elevated response of protein synthesis
to nutrient intake, which is particularly profound
in skeletal muscle. Using novel hormone-substrate clamps,
the feeding-induced stimulation of skeletal muscle
protein synthesis has been shown to involve independent
regulation by both insulin and amino acids whereas
that in other tissues is mediated by either amino acids
or insulin alone. Recent studies have shown that the
high rate of muscle protein synthesis in the neonate
is regulated by the expression and activity of components
of the intracellular signaling pathway that controls
translation initiation. The role of nutrient intake,
insulin, growth hormone, and insulin-like growth factor
I in the regulation of protein degradation, amino acid
oxidation and protein synthesis during growth and development
is also being explored. Other research areas currently
being investigated include the regulation of protein
synthesis during catabolic illness such as sepsis.
The objective of Dr. Ellis' research is to establish
body composition references for the normal biological
diversity of growth in different ethnic groups. As
part of this research, mathematical models are being
developed to describe the temporal and maturational
changes in body composition. Contemporary reference
models for the fetus, infant, child and adolescent
are being developed. The measurements utilized are
state-of-the-art technologies ( 40 K counting, deuterium
and bromine dilution, neutron activation analysis,
dual-energy x-ray absorptiometry, bioelectrical impedance,
body density assessment) that have been or are being
expanded for use in children and infants.
The fundamental objective of Dr. Fiorotto's research
is to identify the in vivo mechanism(s) that confer
to the immature muscle the ability to drive protein
synthesis at an extremely high rate. Ongoing studies
focus on the regulation of mRNA expression, which may
be a limiting factor for protein synthesis in the newly
differentiated myotube, and on the role of locally
produced insulin-like growth factors, which appear
to exert their effect primarily on satellite cell division.
As muscle maturation proceeds, ribosomal abundance
becomes the limiting factor for protein synthesis;
hence, the interrelationship between the regulation
of satellite cell replication and ribosomal RNA transcription
(the limiting step for ribosomal production) will be
examined. A variety of cell and molecular biology techniques
in conjunction with in vivo tracer techniques in infant
animal models, including transgenic mice, the rat and
the pig, are utilized to understand how transcriptional
and translational events contribute to the observed
outcomes.
A second research interest concerns the long-term
functional consequences of impaired muscle growth in
early life. One consequence of the developmentally-linked
regulation of the anabolic processes in the muscle
is that impairment of muscle growth during this phase
of rapid growth (as occur when there is an inadequate
supply of nutrients) chronically compromises muscle
mass. Thus, studies to determine whether the development
of sarcopenia and its sequelae, including obesity and
impaired glucose tolerance, are exacerbated when muscle
growth is compromised in early life are underway. These
include determining if a muscle-specific, plasmid-based
growth hormone-releasing hormone gene therapy that
we have developed can be used to reverse or mitigate
the muscle loss.
Dr. Fisher investigates the development
of food preferences and the controls of food intake
during infancy and early childhood. The broad goal
of her research is to understand how early eating environments
modify young children's eating behavior and health
outcomes. Of particular interest is the parents' role
in selecting foods of the family diet, in serving as
models of eating behavior, and in making child feeding
decisions that affect child food preferences, selection,
and intake patterns. Dr. Fisher has recently demonstrated
that large portion sizes promote overeating at meals
among pre-school aged children. Her research has also
shown that restrictive feeding practices may favor
the development of childhood overweight by focusing
children's attention on restricted foods and promoting
intake of these foods in the absence of hunger. She
is currently investigating the influence of feeding
practices and family eating styles on problematic food
intake regulation and overweight among Hispanic children
and their siblings. Additional research evaluates the
role of maternal feeding practices on food preferences,
regulation of food intake, and development of overweight
during infancy.
Dr. Grusak conducts both plant physiology and
human nutrition research. The plant physiology effort
focuses on identifying the mechanisms and regulation
of short-distance membrane transport and/or long-distance
translocation of organic and inorganic nutrients within
and throughout plants. Of major interest is whole-plant
micronutrient metal nutrition and the interrelationship
of shoot and root factors that regulate expression
in roots of genes relevant to metal acquisition. Emphasis
also is focused on seed developmental biology, using
the model legume, Medicago truncatula, as
a tool to understand how mineral nutrients are transported
to and stored within seeds. Long-term goals are to
characterize the dynamics of nutrient flow within plants,
thereby determining the biophysical/molecular signals
that regulate source-to-sink nutrient partitioning
and to use these data to enhance the nutritional quality
of plant foods. Methodologies utilized range from whole-plant
nutrient partitioning analysis to membrane flux analysis
using radioisotopes to gene discovery and expression
analysis using various molecular techniques.
The human nutrition effort involves the design and
construction of controlled environment systems for
growing and labeling plants with stable isotopes. Protocols
have been developed to generate safe, traceable plant
foods and bioproducts for human consumption. The labeled
foods, in turn, are used to address questions about
absorption and utilization of specific nutrients from
plant food products. Current emphasis is on the bioavailability
of carotenoids and phylloquinone as well as several
mineral nutrients from various vegetable sources.
Dr. Hadsell uses state-of-the-art immunohistochemical
and molecular biological techniques to analyze the
relationships between signaling pathways and in-vivo
developmental processes that occur in the lactating
mammary gland. Transgenic and knockout mouse models
are used to determine the impact of perturbing specific
signaling pathways on regulation of postpartum mammary
cell turnover. Research concerning IGF-I action suggests
that variation in signaling pathway use by the IGF-I
receptor (Igf1r) occurs at different developmental
stages. During lactation, IGF-I relies on cell survival
pathways to inhibit mammary cell apoptosis but, during
earlier stages of development, IGF-I action occurs
through proliferative pathways. Crosses between Igf1r
knockout mice and transgenic mice which overexpress
downstream signaling proteins are used to analyze in
vivo mechanisms of IGF-I action during early mammary
gland development. The impact of overexpression of
IGF-I and of the downstream Igf1r signaling proteins
on lactation and mammary cell apoptosis is being analyzed
both during normal lactation and during prolonged lactation.
Other studies focus on determining the importance of
myc/max/mad family proteins in the regulation of early
postpartum mammary cell proliferation.
The long-term goal of Dr. Haney's research is to understand the molecular and cell biology of lactation. Current work focuses on glucose transport in lactating mammary gland. Glucose is the key substrate for the synthesis of lactose, the major osmotic constituent of human milk and, hence, the major determinant of the volume of milk produced. Glucose also is a key substrate for the synthesis of lipid, the major determinant of the energy content of human milk. Current studies focus on regulation of the amount, activity, and subcellular targeting of GLUT1, the only glucose transporter isoform identified in mammary gland. Established and primary mammary epithelial cell lines as well as humans and rodents are utilized in the studies. Efforts are underway to elucidate the mechanisms of previously observed alterations of glucose transporter targeting during lactation, including sequestration in Golgi-related vesicles and polarization of plasma membrane distribution, and to understand the impact of GLUT1 retargeting and of altered GLUT1 gene expression on lactose synthesis and milk production.
Dr. Haymond's research focuses on the substrate and hormonal regulation of glucose homeostasis in children and adults. In collaboration with Dr. Agneta Sunehag, all of the stable isotopic techniques needed for measuring gluconeogenesis in humans have been developed. Dr. Haymond is exploring the regulation of glucose homeostasis in lactating women and has determined that lactation imposes a 30% increase in demand on the fasting lactating woman and that the human breast is capable of de novo synthesis of both glucose and galactose in the formation of lactose. This contribution of hexoneogenesis contributes nearly 50% of milk lactose production during fasting but, in the fed state, nearly 70 % of lactose is derived from the plasma glucose of the mother.
Dr. Haymond and collaborators also have investigated the impact of dietary fat, carbohydrate and fructose content on nutrient oxidation, insulin sensitivity and glucose homeostasis in normal children and are extending these studies to obese children. Ongoing studies aim to determine the metabolic fate of galactose and fructose as well as their effects on hepatic glucose production and gluconeogenesis. The ultimate goal of this research is to improve care and management of children with hypoglycemia as well as those with both type 1 and type 2 diabetes.
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 w 6 and w 3 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 D -6 and D -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.
All areas of research utilize state-of-the-art
stable isotope and mass spectroscopy techniques as
well as standard anthropometry and nutrient balance
techniques. Some also utilize measurements of
energy expenditure and body composition as well as
cellular and molecular biology techniques.
The major goal of Dr. Henning's research is to understand the factors that control maturation of the epithelium of the small intestine. This is a clinically relevant problem, because immaturity of the intestine accounts for the high suscepti¬bility of infants to diarrhea and for feeding intolerance in preterm infants. Previous research, using rodent models, has shown that there are two distinct regulatory pathways for intestinal maturation: a) a timing mechanism intrinsic to the intestinal tissue; b) a pathway elicited by glucocorticoid hormones which is synergistically enhanced by a second hormone, thyroxine. Current research goals are to determine whether the initiating events of each pathway occur in the epithelial cells or in the underlying mesenchymal cells and to elucidate the regulatory genes which mediate each pathway. Although prior work focused largely on sucrase-isomaltase as a marker of maturation, current efforts focus on a new marker, trehalase, a neglected member of the disaccharidase family. Its importance lies in current efforts of the food industry to use its substrate, trehalose, as an alternative sweetener. Recent research has cloned and mapped the gene for murine trehalase and has identified the human gene. Current studies are assessing the extent to which developmental and glucocorticoid -induced changes of trehalase expression reflect transcriptional activation. Future studies will attempt to identify the transcription factors involved as a first step to dissecting the complete regulatory pathway.
An additional project is designed to identify and characterize intestinal stem cells. Although the presence of these cells has been inferred for many years, they have never been isolated. A novel sorting approach will be deployed to isolate a population of putative intestinal stem cells, together with a graft model to assess their capacity for proliferation and differentiation. If successful, such approaches should have two applications: a) new therapies for various conditions in which the bowel is damaged; b) use of the intestine as a site for gene therapy.
The primary purpose of Dr. Hirschi's research is
to understand, at the cellular and molecular level,
the events leading to blood vessel formation. She is
interested in elucidating regulators of vascular cell
(endothelial and smooth muscle) recruitment, proliferation
and differentiation needed for blood vessel assembly
and maintenance. Mechanisms by which soluble effectors
such as retinoids and TGF-? as well as cell-cell junctional
components such as gap junctions modulate vascular
cell phenotype and cell cycle progression will be defined.
In vitro co-culture systems are used to study interactions
between vascular cells and their precursors and in
vivo regulation of blood vessel assembly is studied
in murine embryo culture and transgenic mouse models.
Another research focus concerns the potential of
adult stem cells to contribute to neovascularization
in response to tissue injury and growth. Bone marrow
transplantation and localized delivery techniques are
used to study mechanisms by which adult stem cells
are recruited, induced to differentiate into vascular
cells, and functionally integrated into existing vascular
networks. Insights gained from these cell and developmental
studies are applicable to the optimization of clinically
relevant treatments including autologous vascular cell
and gene therapy, assembly of blood vessel grafts,
and vascularization of engineered tissues.
The long-term goal of Dr. Hirschi's research is to understand the components of ion homeostasis and calcium signal transduction in plants and to assess the role of these genes in plant growth and adaptation. Using a combination of approaches, he is attempting to characterize the expression and physiological function of calcium transporters and 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. The ensemble of ion transporters and their regulatory molecules have been characterized and identified, thus allowing ion storage, signal transduction events, and the environmental constraints of traditional agricultural practices to be manipulated.
Dr. Jahoor's research interests
include nutritional requirements during growth and
development and in different pathological states, interrelationships
between protein and energy (glucose and fat) metabolism
in normal and pathological states, in vivo protein,
amino acid(s), urea, glucose and lipid metabolism,
and the development of stable isotope tracer methodologies
to study in vivo substrate metabolism. Current
efforts include development and use of stable isotope
tracer methodologies to investigate the in vivo metabolism
of proteins, amino acids, urea, glucose and lipids
in both animals and humans. An area of primary interest
is the impact of the metabolic response to the stress
of infection and injury on nutritional requirements
during early growth and development. Studies are being
performed in both animals and humans to determine how
stress alters protein and energy metabolism and the
role of stress in the precipitation of severe protein-energy
malnutrition. Other studies concern the effect of surgical
trauma on protein and amino acid metabolism of premature
neonates. Special emphasis is placed on the role of
stress-induced alterations in the hormonal milieu as
one of the major mediators of the deranged metabolic
response to infections and injury. Stress-induced changes
in the partitioning of nitrogen for synthesis of muscle
proteins, acute phase proteins, and nutrient transport
proteins also are being investigated.
Dr. Karpen's research focuses on mechanisms for
regulation of the Sonic Hedgehog signaling pathway
which is fundamental for early embryonic patterning
of nearly every organ system of the developing fetus
and is conserved from Drosophila to humans.
Her lab has focused primarily on regulation of the
Hedgehog receptor complex, comprised of the two large
transmembrane proteins, Patched and Smoothened. Mutation
analysis has revealed several domains of each of these
proteins that are important for appropriate receptor
complex formation, receptor trafficking and function.
Current efforts are directed at studying these domains
in relation to the binding of the Sonic Hedgehog ligand
and signal transduction in the pathway. Work over the
past two years has shown a link between Patched, cholesterol
and the structural protein, caveolin-1. Recently published
data confirm that Patched and caveolin-1 interact directly
via a short, highly conserved amino acid motif found
in each protein and that caveolin-1 is involved in
the transport of Patched to lipid rafts on the membrane.
Cholesterol, a key component of lipid rafts, seems
to play an integral role in transport of the Hedgehog
receptor to these specialized membrane microdomains
and ongoing studies focus on defining its role in receptor
function and signal transduction in this pathway.
Dr. Karpen is actively pursuing two major research
interests. The first concerns molecular regulation
of hepatobiliary transporter genes. Over the past few
years, it has become apparent that a wide variety of
endogenous and exogenous substances are transported
into and out of the hepatocyte via specific transporters.
Thus, research has focused on understanding the nuclear
factors that regulate the expression of these transport
genes. A particular interest is the role of regulable
factors such as nuclear receptors. The aim of this
research is to enhance understanding of normal hepatobiliary
physiology as well as the adaptive response to cholestasis,
a condition in which elevated concentrations of intracellular
bile acids can cause and exacerbate ongoing liver damage.
Recent research exploring how the hepatocyte responds
to cholestasis has shown that bile acids themselves
act as gene regulators.
The second research interest concerns extracellular
ATP activation of hepatocyte proliferation. Extracellular
ATP activates specific cell surface receptors that
transduce a variety of intracellular signals, one of
which appears to be events linked to hepatocyte proliferation.
Research in this area focuses upon exploring signal
transduction and nuclear regulatory pathways that may
represent a novel fundamental mechanism for the regulation
of gene expression and growth in the liver.
Dr. Karsenty is interested in two different areas
of skeleton biology. The first concerns elucidation
of the transcriptional mechanisms controlling cell
differentiation in chondrocyte and osteoblast lineages.
Through a molecular biology approach, a gene that controls
the entire cascade of osteoblast differentiation has
been identified in mice and humans. This gene, Cbfa1,
is a mammalian homologue of a drosophila gene runt.
It not only controls osteoblast differentiation throughout
the skeleton but also controls chondrocyte differentiation
in some parts of the skeleton. To date Cbfa1 is the
only factor known to control differentiation of both
osteoblasts and chondrocytes, two cell types long thought
to have a common progenitor. More recent efforts have
shown that Cbfa1 is required for osteoblast function,
namely bone formation after birth. Thus, Cbfa1 is both
a determination factor during development and a regulator
of skeleton physiology postnatally. Current efforts
focus on a downstream gene of Cbfa1 which also encodes
a transcription factor. This project relies on genetic
and biochemical approaches.
Despite the central role that Cbfa1 plays during
skeletogenesis, there is a five-day delay between the
initiation of Cbfa1 expression at E10 during mouse
development and the appearance of the first osteoblast
at E15. This could be explained by two different mechanisms;
Cbfa1 either initiates the expression of an activator
of cell differentiation and/or Cbfa1 function is inhibited
by another protein. A second osteoblast-specific transcription
factor has recently been identified and knock-out of
this factor results in a major decrease in the number
of osteoblasts per bone. Current efforts are aimed
at identifying the mode of action of this factor and
its relation to Cbfa1. A transcriptional inhibitor
of Cba1 called iCbfa1 also has been identified. Its
deletion corrects the loss-of-osteoblast phenotype
of the Cbfa1-deficient mice. Thus, other experiments
are aimed at identifying the mode of action of this
factor.
More recently, largely by serendipity, a Cbfa1-dependent
pathway to control osteoblast proliferation and function
was uncovered by observation of a decrease in bone
formation in mice and humans in which the gene encoding
Lrp5 is inactivated. Lrp5 is a receptor for the Wnt
proteins and the low bone mass phenotype of the Lrp5-deficient
mice suggest that Wnt proteins are involved in osteogenesis.
This new line of research is developing through the
use of molecular biology and genetic tools.
The second major area of study focuses on the physiology
of the skeleton, specifically the genes and the genetic
pathways controlling bone remodeling and bone mineralization.
This line of research stems from the belief that the
combination of molecular biology and mouse genetics
provides sophisticated tools that allow the study of
physiology and pathophysiology of degenerative diseases.
Using two mutant mouse strains, leptin has been determined
to be a potent inhibitor of bone formation through
a hypothalamic relay. The inhibitory action of leptin
is so powerful that mice deficient in leptin or its
receptor maintain a high bone mass even when gonadectomized
(gonadal failure is the most frequent cause of bone
loss or osteoporosis in mammals). Currently, a genetic
approach is being used to identify the mediators of
leptin in bone remodeling. Additional studies are exploring
whether this novel hypothalamic regulation of physiology
can be used to establish new therapeutic approaches
for bone loss diseases. Finally, the role of other
hormones acting through the hypothalamic regulatory
loop is being explored.
Another project of molecular physiology explores the
postulate that absence of mineralization in all tissues
is an active physiologic function whereas bone mineralization
is a passive process or a default pathway. The function
of four different genes is currently being studied
to establish this concept and to establish a genetic
cascade to explain the absence or presence of mineralization
in any tissue.
The major goal of Dr. Moore's research is to understand
the functions of the newer members of the nuclear hormone
superfamily. Current efforts focus on three that have
emerged as key regulators of metabolic pathways in
the liver: CAR, FXR and SHP. He and colleagues have
found that CAR functions to regulate the response of
the liver to potentially toxic foreign compounds, such
as drugs and environmental pollutants, collectively
termed xenobiotics. Activation of CAR by specific xenobiotic
stimuli results in an increased ability of the liver
to metabolize and eliminate such compounds. CAR also
is activated by an endogenous toxic product, bilirubin,
and this activation also results in an increased rate
of bilirubin metabolism and clearance. Although these
CAR-dependent responses are generally protective, CAR
activation also can be deleterious. For example, activation
of CAR by very high doses of acetaminophen increases
production of a toxic acetaminophen metabolite with
severe liver toxicity and blocking CAR activity prevents
the hepatotoxic effects of an acetaminophen overdose.
The recent findings that chronic activation of CAR
by a class of compounds called non-genotoxic carcinogens
results in liver tumors suggests that this hepatocarcinogenesis
is a consequence of direct effects of CAR on both hepatocyte
proliferation and apoptosis; thus, current studies
are exploring the molecular mechanisms for these effects.
FXR is a recently identified receptor for bile acids,
which are downstream metabolites of cholesterol produced
in the liver. Although they were previously thought
of mainly as detergents to dissolve dietary lipids,
they now appear to be important regulators of lipid
homeostasis as well. Activation of FXR by high levels
of bile acids induces expression of SHP, an unusual
orphan receptor that lacks a DNA binding domain. SHP
acts to repress transcriptional activation by several
other nuclear receptors, resulting in decreased expression
of key metabolic target genes. Since one of these is
the rate limiting enzyme for bile acid production,
this FXR/SHP pathway accounts for the negative feedback
regulation of bile acid biosynthesis. The FXR/SHP Pathway
also mediates beneficial effects of bile acids on triglyceride
levels by decreasing expression of SREBP-1c, a transcription
factor that promotes expression of a variety of lipogenic
enzymes. FXR also regulates the expression of a number
of other proteins involved in cholesterol and bile
acid homeostasis. Prompted by this central regulatory
function of FXR and its ability to respond to a wide
range of bile acids and other ligands, we screened
a number of compounds that alter cholesterol levels
by unknown mechanisms for effects on FXR. This led
to the identification of guggulsterone, a plant derived
steroid that lowers LDL cholesterol by antagonizing
FXR. The biochemical basis for the cholesterol lowering
effects of guggulsterone are now being studied. Pharmacologic
and mouse knockout approaches are used to define the
metabolic regulatory functions of the nuclear hormone
receptors.
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.
Dr. Nichols' research has focused upon the adaptive
alterations of physiologic function in malnourished
infants. In recent years, this work has been directed
toward the enteric mucosal adaptations of severely
malnourished infants with a specific focus on brush
border hydrolases necessary for carbohydrate digestion.
Extending this investigation to the molecular level,
the mucosal enzyme glucoamylase cDNA as well as the
entire gene have been cloned and sequenced. Structurally,
the glucoamylase gene is very similar to that of sucrase,
both of which are needed to digest starches. Recent
studies include investigations of the transcription
and translation of these brush border enzyme genes
in children with chronic abdominal pain. Research conducted
in children with chronic abdominal pain, utilizing
tissues obtained by endoscopic biopsy, showed that
26% had low glucoamylase activities. A mouse knockout
model of glucoamylase deficiency has been developed
and the physiologic deficits caused by this are currently
under study. Glucoamylase and sucrase are regulated
during development and in response to changes in the
level of starch in the diet. The present focus is on
understanding the molecular mechanisms by which these
two related genes are co-regulated.
Dr. Nicklas's research interests encompass both
the epidemiological and interventional aspects of chronic
disease prevention and health promotion. Two general
questions of interest include: How do eating behaviors
and other lifestyles influence the development of chronic
disease risk factors early in life? What are the behavioral
factors influencing the development of adverse lifestyles
early in life? These questions must be answered before
effective interventions to prevent chronic disease
risk can be developed. Specific areas of interest include:
1) environmental factors influencing the development
of eating patterns early in childhood; 2) how these
eating patterns relate to the onset of obesity, cardiovascular
disease, cancer and type 2 diabetes; 3) effective intervention
strategies for changing and maintaining healthful behaviors,
particularly in children and adolescents. Dr. Nicklas's
work has provided data on the eating habits and dietary
intakes of children as it relates to chronic diseases
over a span of 25 years. These data have provided the
rationale and foundation for early intervention programs,
national dietary guidelines, and public policy. In
addition to epidemiologic investigations, she has been
involved in the design and evaluation of nutrition
intervention programs for children, adolescents, and
families.
Dr. Rijnkels' primary research goal is to understand
the regulation of the casein genes and the genomic
domain in which these genes reside. Caseins constitute
the major nutritional proteins in milk and supply basic
amino acids, calcium, phosphates and bioactive peptides
( e.g. anti-microbial and opioid). Genomic
approaches are used to study the transcriptional regulation
of the casein gene cluster region. This combines three
lines of research: The study of the chromatin structure
and remodeling in the casein gene cluster region related
to tissue type and development, using Chromatin Immuno
Precipitation (ChIP) assays; Computational approaches
to identify evolutionarily conserved regions with potential
regulatory function and the trans-acting factors that
might bind them; The functional analysis of potential
regulatory regions in transgenic mice.
As the casein-cluster region harbors a number of
non-casein genes that potentially share functional
properties as well as spatial expression patterns and
evolutionary ancestry, we also study these genes.
Dr. Rosen's research objectives 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. In the mouse mammary gland, there are several
critical periods of development: Ductal proliferation
and branching that occur during sexual maturity; Lobuloalveolar
proliferation that occurs during pregnancy; Terminal
differentiation and lactation; Involution, characterized
by increased apoptosis and extensive tissue remodeling.
Dr. Rosen is studying the role of systemic hormones
( i.e., prolactin,
glucocorticoids, estrogens, progestins) and local growth
factors, including members of the Wnt and Fgf 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. Gene arrays and subtractive hybridization techniques
are being employed to identify downstream targets of
these transcription factors. Methods that permit the
analysis of both gain and loss of specific gene function
in the mammary gland also have been developed. Studies
in mouse models have been translated to the analysis
of alterations in the levels of these factors in breast
cancer biopsies. Finally, transgenic mouse models that
mimic highly aneuploid human breast cancers have been
developed using a gain-of-function p53 mutant. Studies
using these models to define the mechanisms responsible
for genomic instability are in progress.
Dr. Shulman's primary research interest concerns
the development and adaptation of the gastrointestinal
tract of the premature infant. A specific interest
is the maturation of carbohydrate digestion and absorption
mechanisms. Current goals are to develop strategies
that will maximize the function of the immature or
impaired gastrointestinal tract ( e.g. , short
bowel syndrome) and therapeutic treatments that will
enhance gastrointestinal tract development and function.
Studies currently being conducted in premature infants
focus on: 1)The interaction between digestion and absorption
of carbohydrates and other nutrients; 2)The ontogeny
of carbohydrate digestion and absorption in terms of
hydrolysis and/or transport; 3)The relationship between
digestive and absorptive function and the mechanisms
presumably regulating these functions ( e.g. ,
glucose transport and transporter mRNA); 4)The factors
that contribute to feeding intolerance; 5)Hormonal
influences on the growth and adaptation of the gastrointestinal
tract.
Dr. Smith's research focuses on the mechanisms of
neutrophil transendothelial migration - specifically the mechanisms
of leukocyte activation and adhesion and the phenotypic
changes neutrophils undergo following transmigration.
Ongoing studies have demonstrated significant kinetic
distinctions between LFA-1 and Mac-1 following activation
by CXC chemokines, a role for PI3Kinase in the activation
of LFA-1 but not Mac-1, and markedly increased synthesis
of oncostatin M by transmigrated neutrophils. In addition,
microarray techniques have been used to indicate significant
new gene expression in neutrophils following stimulation
with IL-15, a cytokine expressed by inflamed endothelial
cells. Finally, studies to confirm the kinetics of
expression of several of the intriguing genes identified
by array analysis are underway.
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".
Dr. Sunehag's primary research interest concerns
glucose metabolism in children. A longstanding research
focus has been glucose homeostasis of prematurely born
infants during their first days of life. Currently,
she is investigating how these immature infants utilize
parenteral nutrients to produce glucose via the gluconeogenic
pathway. The ultimate goal of this research is to define
a mixture of parenteral nutrients that both maintains
normoglycemia and promotes normal growth. A second
research focus concerns the effects of dietary macronutrient
content and exercise on parameters of glucose metabolism
(glucose production, gluconeogenesis and insulin sensitivity)
in non-obese and obese pre-pubertal children and adolescents.
She also is involved in studies of glucose homeostasis
in lactating mothers and the metabolism of galactose
and fructose. Dr Sunehag utilizes compounds labeled
with stable isotopes and gas chromatography - mass
spectrometry to measure the dynamic parameters of glucose
metabolism and is interested in resolving methodological
issues regarding these techniques.
Dr.
Tong's research concerns adipose tissue development,
which may provide clues to the molecular mechanisms
of obesity and type 2 diabetes later in life. His previous
work demonstrated that both GATA transcription factors
are expressed in preadipocytes and that their expression
disappears in mature fat cells. GATA transcription
factors suppress adipocyte differentiation through
the interference of two critical regulators, PPAR? and
the C/EBP family of transcription factors. GATA also
forms protein complexes with other proteins, some of
which ( e.g. , C/EBP, Rb and Trap220) also
are known to be involved in the process of fat cell
formation, such as current research focuses on characterization
of the components and dynamics of the GATA protein
complexes during adipogenesis.
Another line of research concerns the function of
the sirtuin family of deacetylases, the mammalian homologues
of yeast Sir2 gene, which mediates the effect of caloric
restriction on life span extension. Initial experiments
have demonstrated that mammalian sirtuins play roles
in white adipocyte differentiation and brown adipocyte
adaptive thermogenesis.
. Dr. Van den Veyver's primary research interest
is the role of DNA methylation in epigenetic regulation
of gene expression during development. She participated
in studies showing that Rett syndrome, an X-linked
dominant neurodevelopmental disorder, is caused by
mutations in MECP2. This gene encodes methyl-CpG-binding
protein 2, which plays a role in transcriptional silencing
of other genes when they are methylated at their promoters.
To better understand the role of DNA methylation in
development, current studies focus on the effects of
varying dietary levels of methyl donor agents (folic
acid, betaine) on DNA methylation and gene expression
during development. These studies utilize large genomic
screens in mouse models and cell culture systems. In
collaboration with others, she is studying the effects
of such treatments on DNA methylation and correlating
these effects with phenotypic effects in Rett syndrome.
This work is relevant for the understanding not only
of Rett syndrome but also of other common birth defects,
(e.g., neural tube defects) as well as the influence
of intrauterine environment on gene expression later
in life. Additional laboratory projects focus on identification
and functional analysis of genes for other X-linked
dominant disorders and for recurrent familial hydatidiform
moles.
Dr.
Waterland's research focuses on the basic biologic
mechanisms by which the pathogenesis of several adult-onset
diseases can be influenced by nutrition in early life.
One probable mechanism is through early nutritional
effects on epigenetics, i.e. self-perpetuating gene
regulatory systems that are not dependent on DNA sequence
alterations. He is particularly interested in the methylation
of cytosine residues on both strands of palindromic
CpG dinucleotides in genomic DNA. Mammalian one-carbon
metabolism, which provides the methyl groups for biological
methylation reactions, is highly dependent on dietary
substrates and co-factors. The requirement to establish
and maintain genomic methylation patterns during early
development may therefore make it more critical to
maintain appropriate levels of these diet-derived components
at that time than during later life. He and colleagues
have demonstrated that dietary methyl donor supplementation
of viable yellow agouti ( A vy ) mice during
early development increases CpG methylation at the agouti locus.
The overall hypothesis is that maternal dietary methyl
donor supplementation before conception and during
pregnancy alters DNA methylation of specific genomic
regions in the early embryo and that these alterations
persist to adulthood. Because epigenetic dysregulation
is implicated in a broad range of human disease, such
induced epigenetic alterations may enable early nutrition
to influence adult metabolism and chronic disease susceptibility. Leonard
E. Weisman, MD (lweisman@bcm.tmc.edu)
Dr. Weisman's research includes both laboratory
and clinical studies related to neonatal immunity,
including the effects of neonatal neutrophil function
and/or immoglobulin (parenteral, enteral or transplacental)
on common infectious agents (e.g., Streptococcus agalactiae,
Staphylococcus epidemidis, Ureaplasma urealyticum,
respiratory syncytial virus) and the effects of modulation
of neonatal neutrophil and/or immunoglobulin function
on these agents. A multi-center NIH-sponsored project
focusing on the protective levels of maternal antibody
against early-onset invasive group B streptococcal
disease in neonates was just completed and a single-center
NIH-sponsored project focusing on determining the risk
factors for late-onset invasive group B streptococcal
disease in neonates is nearing completion. Dr. Weisman
also directs the clinical and laboratory evaluation
of an anti-Staphylococcal humanized monoclonal antibody
for the prevention and treatment of infection.
Dr.
Wong's major research efforts focus on prevention
of childhood obesity and dietary supplementation to
prevent chronic diseases. He recently completed
a project funded by the Texas Department of Health
documenting the prevalence of and risk factors for
childhood obesity in the Houston Independent School
District , the largest public school district in Texas with
students of diverse ethnic and socioeconomic backgrounds. A
project to determine the effectiveness of an after-school
physical activity program in preventing obesity among
Hispanic children is planned.
He also is the project director of
a USDA-funded $4.5 million, multi-center, randomized,
double-blind, placebo-controlled study to document
the safety, efficacy, and optimal dosage of soy isoflavones
to prevent osteoporosis in postmenopausal women. In
addition, he is principal investigator of 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. |
