Darryl L. Hadsell,
Ph.D.
Current evidence supports the idea that insulin-gene family members
are necessary for all aspects of mammary gland development and lactation.
Despite this, the mechanisms by which these peptides regulate mammary
gland function are poorly understood. Research within Dr. Hadsell’s
laboratory focuses on three main goals. The first is to understand
the specific mechanisms through which the receptors for insulin
(IR) or IGF-I (IGF-IR) influence mammary gland development and/or
lactation. The second is to understand the mechanisms through which
nutrient availability influences mammary gland development and/or
lactation. The last is to understand how these factors interact
at the transcriptional level to allow normal mammary gland development
and lactation. The combined use of transgenic and knockout mice,
tissue grafting strategies, and in-vitro cell culture models to
modify IR or IGF-IR activity has provided insights into the mechanism
through which apoptosis is regulated within the mammary gland. These
strategies have also led to a focus on putative insulin-responsive
transcription factors as a means to define insulin-dependent milk
protein gene expression.
Peter M. Haney, M.D., Ph.D.
Dr. Haney's long-term research goal is to understand the molecular
cell biology of lactation. Human milk is recognized as the ideal
source of nutrition for infants, but the mechanisms and regulation
of milk secretion are poorly understood at the cellular and molecular
level. Current work is focused on glucose transport in the lactating
mammary gland. Dr. Haney is studying the regulation of the amount,
activity, and subcellular targeting of GLUT1, the only glucose transporter
isoform identified in the mammary gland, in established and primary
mammary epithelial cell lines, as well as in humans and rodents.
Efforts are under way to elucidate the mechanisms of altered glucose
transporter targeting, including Golgi sequestration and polarization
of plasma membrane distribution, that he has observed during lactation.
He will examine how GLUT1 gene expression and subcellular targeting
regulate the synthesis of lactose. Dr. Haney has observed a novel
protein, structurally similar to GLUT1, that resides in the Golgi,
and is expressed only during lactation. He is pursuing the purification
of this protein, the cloning of its cDNA, and the characterization
of its possible role in regulating the targeting of GLUT1.
Morey W. Haymond, M.D.
Dr. Haymond’s research focus is to delineate, and ultimately
manipulate, the hormone and substrate factors that regulate the
absorption, assimilation, mobilization and disposal of carbohydrates
in infants and children. The delicate balance of nutrient availability
to meet the energy and growth needs of children is frequently disturbed
as a result of chronic disease, infection, trauma and/or organ failure.
In addition, the increasing incidence of both type I and type II
diabetes provides unique opportunities to study the effects of insulin,
insulin resistance and obesity on macronutrient assimilation in
children. Specific studies utilize a variety of stable isotopic
tracer techniques to estimate insulin sensitivity, absorption of
carbohydrates, proteolysis, protein synthesis, gluconeogenesis,
carbohydrate disposal, and protein and fat metabolism. Studies currently
under way explore the impact of diet composition (fat and carbohydrate)
on glucose homeostasis and macronutrient accretion in normal and
obese children, the impact of lactation on glucose homeostasis,
the precursors for lactose production by the mammary gland as well
as the factor(s) which regulate it, and the regulation of galactose
and fructose metabolism and the effects of co-ingestion of glucose.
William C. Heird, M.D.
Dr. Heird’s studies focus on the nutrient needs of low-birth-weight
infants and other infants and children with special needs as well
as ways of meeting these needs, including the specific amino acid
needs of those who depend upon parenterally delivered nutrients.
An additional interest concerns the metabolism of essential fatty
acids during infancy and childhood, including the role of long-chain
polyunsaturated fatty acids in this population.
Karen K. Hirschi, Ph.D.
Blood vessel formation is essential for normal growth and development,
and it plays a central role in the progression of prevalent pathologies
including atherosclerosis, tumor angiogenesis and diabetic retinopathy.
Dr. Karen Hirschi is interested in understanding how blood vessels
are assembled; elucidating the regulators of cellular recruitment,
proliferation and differentiation needed for vessel formation and
maintenance; and exploring the role of such effectors in prevention
and treatment of vascular pathologies. She is also interested in
examining the potential of stem cells derived from adult tissues
to give rise to vascular cells in vivo, and utilizing such cells
to enhance or suppress normal and pathological neovascularization.
These issues are being addressed using novel in vitro coculture
systems, murine embryo culture, and transgenic mouse models
Kendal Hirschi, Ph.D.
Unable to flee when challenged by an environmental threat, plants
must adapt by altering their physiology. Calcium ions play a central
signaling role in the cascade of events that empower plant cells
to initiate these responses. Dr. Kendal Hirschi has utilized mutants
in budding yeast to isolate plant genes that regulate intracellular
calcium levels. Future work in his lab will be directed toward molecular
and genetic approaches to study calcium transport and signaling
in the model plant Arabidopsis thaliana.
Judy A. Hopkinson, Ph.D.
Dr. Hopkinson’s research goal is to define physiological and
behavioral factors associated with optimal breastfeeding practices.
To achieve this goal, her research focuses on the following areas:
the impact of lactation on maternal and infant physiology, with
special emphasis on bone metabolism; the identification of cultural
factors that limit breastfeeding duration and/or exclusivity; the
characterization and etiology of breast and nipple discomfort encountered
by breastfeeding women; and the evaluation of intervention strategies
and counseling techniques designed to increase optimal breastfeeding
behaviors.
Farook Jahoor,
Ph.D.
Dr. Jahoor’s research focuses on the intermediary metabolism
of macronutrient fuels. One area of primary interest is the altered
metabolic response to the stress of infections, and its impact on
nutritional requirements during early growth and development. Studies
are being performed in both animals and humans to determine how
stress alters protein (and specific amino acids), carbohydrate and
lipid metabolism. Another area of research looks at how the production
of antioxidants and proteins involved in the immune response is
affected by conditions such as protein-energy malnutrition, HIV
infection, aging and diabetes mellitus. Specific studies focus on
the metabolism of glutathione, cysteine, acute-phase proteins and
nitric oxide. Stress-induced changes in the partitioning of nitrogen
for the synthesis of muscle proteins, acute-phase proteins and nutrient
transport proteins are also being investigated. Dr. Jahoor is also
involved in the development and use of different stable isotope
tracer methodologies to investigate intermediary metabolism.
Craig L. Jensen, M.D.
Dr. Jensen's research is directed toward determining the optimal
intakes of polyunsaturated fatty acids for term and preterm infants.
The ability of infants to synthesize longer-chain n-3 and n-6 polyunsaturated
fatty acids from their precursors, alpha-linolenic and linoleic
acids, respectively, is being investigated using stable isotope
techniques. The effects of different dietary intakes of essential
fatty acids on biochemical and functional outcomes in both term
and preterm infants are being assessed.
Heidi Karpen, M.D.
Dr. Karpen’s research involves the study of Patched, a tumor
suppressor gene responsible for Gorlin Syndrome. Patched is a member
of the Sonic Hedgehog signaling pathway, critical for early embryonic
patterning and development. Dr. Karpen is using mutations identified
in Gorlin patients and sporadic basal cell carcinomas to define
functional domains important for protein trafficking and function.
The goal of this research is to better understand mechanisms of
aberrant embryonic development and cancer formation so that targets
for intervention may be identified.
Gerard Karsenty, M.D., Ph.D.
Dr. Karsenty’s research focus is on the regulation of bone
remodeling by hormones that also affect body weight and reproduction.
To that end, Dr. Karsenty is using mutant mouse strains in which
either specific hormones or their receptors are deleted. He currently
is studying how leptin controls bone mass. He hopes to determine
whether leptin acts through a different set of secondary messengers
to regulate body weight and bone mass, using mouse models generated
in the laboratory. He also is exploring the concept that antagonizing
the leptin pathway may be a way to treat osteoporosis without affecting
body weight. Lastly, he is studying other hormones that may regulate
body weight and bone mass.
Alexandre
Lapillonne, M.D., Ph.D.
Dr. Lapillonne’s primary research interest is to determine
if, and how, an early nutritional event may have long-term effects
on quality of growth, metabolic functions and development. His work
has focused on the most common nutritional problems during early
life: the effect of intrauterine growth on body composition and
postnatal growth; the effects of specific nutrients on gene transcription;
and how alterations in gene transcription affect growth and body
composition. His current research focuses specifically on the effect
of n-3 polyunsaturated fatty acids on weight gain, body composition,
fat oxidation, energy expenditure and transcription of genes controlling
lipid oxidation and thermogenesis. A planned project will assess
how and when in early life, optimization of protein intake will
maximize catch-up growth and neurological development of very-low-birth-weight
infants. Each project employs a wide variety of tools of in vivo
investigation (e.g., indirect calorimetry, body composition assessment,
stable isotope methodologies) as well as in vitro methods such as
DNA microarray analysis. The overall goal of Dr Lapillonne’s
research is to optimize the nutritional management of extremely
low-birth-weight infants in order to overcome long- lasting effects
on growth and development.
Carlos Lifschitz, M.D.
Dr. Lifschitz currently is conducting a multicenter study aimed
at determining the effect of growth hormone on intestinal adaptation
in children with short bowel syndrome. His future plans include
the initiation of a Houston study that will focus on the relationship
between food allergy and gastrointestinal dysfunction in children.
Ronald L. McNeel,
M.S.
Ronald McNeel studies the influence of long-chain fatty acids on
adipocyte growth and differentiation. These studies focus on the
in vitro use of isolated stromal-vascular cells to evaluate factors
regulating the differentiation process in the presence of long-chain
fatty acids. Mr. McNeel is studying the binding affinities of these
long-chain fatty acids to the ligand-binding region of the PPAR-RXR
heterodimer. The goal is to further characterize the molecular mechanisms
by which fatty acids influence adipocyte differentiation. In a second
research area, Mr. McNeel is studying the association of polymorphisms
in adipocyte-specific genes with obesity measures, using a case-control
epidemiological design.
Harry J. Mersmann, Ph.D.
Adipocyte growth and differentiation are regulated by various hormones
and growth factors. Beta-adrenergic receptors are among the major
regulators of adipocyte metabolism. Dietary components may alter
the pattern of adipocyte growth and differentiation. Dr. Mersmann’s
laboratory has studied the influence of the stage of development
and of dietary factors on adipocyte beta-adrenergic receptors. Currently,
the focus of his efforts is on adipocyte development. Porcine adipocyte
precursor cells may be isolated from adipose tissue and when grown
in culture in vitro under the proper conditions, differentiate to
adipocytes. He has used this system to evaluate factors regulating
the differentiation process and the influence of dietary components
of differentiation. In addition to mRNA for the beta-adrenergic
receptors, mRNA for various transcription factors that regulate
differentiation (e.g., C/EBP-alpha or PPAR-gamma) and mRNA for key
proteins that characterize the adipocyte (e.g., lipoprotein lipase
and aP2) are being measured. He is particularly interested in the
role of individual fatty acids in the stimulation or inhibition
of adipocyte differentiation.
David D. Moore, Ph.D.
The receptors for retinoic acid, thyroid hormone, steroids, and
other potent biological regulators belong to a nuclear hormone receptor
superfamily. This family also includes a number of additional proteins
called orphan receptors, which do not have known ligands. The conventional
receptors regulate a variety of processes in developing and adult
animals. The orphans are less well characterized, but it is thought
that they also play important roles in diverse areas. The broad-ranging
effects of these proteins are a consequence of their function as
ligand-dependent, or in some cases, ligand-independent transcription
factors. The main goal of Dr. Moore’s laboratory is to understand
the mechanisms of action of the members of this superfamily. Toward
this aim, he has identified a number of proteins that interact with
both conventional and orphan receptors, and he is characterizing
their functions.
Kathleen J. Motil, M.D., Ph.D.
Dr. Motil's studies focus on estimating dietary protein and amino
acid needs of lactating women and adolescents and elucidating the
mechanisms that underlie increased nutrient needs for milk production.
Using stable isotope techniques, she has found that lean body mass
of adult women is preserved during lactation because of the downregulation
of rates of whole body protein turnover, synthesis and degradation,
suggesting that nutrient conservation occurs because of the needs
of milk production. In contrast, lean body mass of adolescents increases
during lactation at the expense of a reduction in milk production.
Dr. Motil’s studies also focus on estimating the dietary protein
and energy needs of girls with Rett syndrome and elucidating the
mechanisms that underlie the universal finding of growth failure
in this disorder. Using stable isotope techniques and whole-room
calorimetry, she has found that involuntary motor movements associated
with Rett syndrome do not increase rates of energy expenditure,
and that poor growth results from reduced dietary energy intakes
associated with oropharyngeal and gastroesophageal dysfunction.
Paul Nakata, Ph.D.
Calcium in plants is sequestered as a complex with other substances
such as oxalates, phytates, fiber, fatty acids, proteins and other
anions. Some of these substances (oxalates and phytates) are considered
antinutrients, and render the calcium in plant foods unavailable
for nutritional absorption by the human. The purpose of Dr. Nakata's
research program is to elucidate the mechanism regulating calcium
partitioning and sequestration in plants. The acquired information
will be applied toward the rational design of strategies to enhance
calcium abundance and bioavailability in plant food products.
Buford Nichols, M.D.
The ultimate objective of the research being conducted by Dr. Buford
Nichols is the determination of the mechanisms by which dietary
starch interacts with the gene expressing maltase-glucoamylase.
Maltase-glucoamylase is the gatekeeping enzyme that determines small
intestinal starch digestion into glucose or, by default, colonic
fermentation into short-chain fatty acids. The function and regulation
of maltase-glucoamylase are under investigation in knockout mice
and children with deficient starch digestion. The mechanism of regulation
is under study in a mouse intestinal cell line producing maltase-glucoamylase.
Theresa A. Nicklas, Dr. P.H.
Dr. Nicklas’ research focuses on the epidemiological and intervention
aspects of chronic disease prevention and health promotion. Specifically,
how do eating behaviors and other lifestyles influence the development
of chronic disease risk factors early in life? Also, what are the
behavioral factors influencing the development of adverse lifestyles
early in life? Areas of interest include: (1) environmental factors
influencing the development of adverse eating patterns early in
childhood; (2) how these eating patterns relate to the onset of
obesity, cardiovascular disease, cancer and type 2 diabetes; and
(3) effective intervention strategies for changing and maintaining
healthful behavior changes, particularly in children and adolescents.
A current area of research involves a detailed investigation of
the relationship between eating patterns and obesity in children
and young adults. Planned studies include an examination of family
and caregiver influences on fruit, juice and vegetable consumption
by preschool children from different ethnic groups, and a behavior-based
intervention aimed at favorably influencing food preferences and
consumption by African-American and Hispanic-American preschool
children attending Head Start.
Jeffrey M. Rosen,
Ph.D.
The research objectives of Dr. Rosen’s laboratory are to elucidate
the mechanisms regulating the normal development of the mammary
gland, including the hormonal control of milk protein expression,
and to determine how these regulatory mechanisms have deviated in
breast cancer. Critical periods of development in the mouse mammary
gland include the ductal proliferation and branching that occur
during sexual maturity, lobuloalveolar proliferation that occurs
during pregnancy, terminal differentiation that results in lactation,
and involution characterized by increased apoptosis and extensive
tissue remodeling. Studies of the role of systemic hormones (e.g.,
prolactin, glucocorticoids, estrogens and progestins) and local
growth factors, including members of the Wnt and Fgf families, on
each of these processes are under way. The roles of specific transcription
factors and their dominant-negative isoforms, including members
of the C/EBP, Stat and NF I families, also are being examined using
transgenic and knockout mouse models. Gene arrays and subtractive
hybridization techniques are employed to identify downstream targets
of these transcription factors. Postnatal mammary gland development
is being studied in knockout mice displaying late embryonic or neonatal
mortality by transplantation of mammary epithelium into the cleared
mammary gland fat pad of syngeneic recipients. In addition, methods
that permit the analysis of both gain and loss of specific gene
function selectively in the mammary gland have been developed. Finally,
transgenic and knockout mouse models are being used to elucidate
the changes in normal signal transduction pathways that are involved
in the progression from the normal mammary gland to preneoplasias,
as well as the role of mutant p53 in genomic instability and the
development of aneuploidy.
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