Download Andreas Matouschek

Faculty Laboratories Available for Undergraduate Research
Neurobiology & Physiology
Ravi Allada (2121 Pancoe)
Why do we need to sleep? Why do we wake up in the morning and go to sleep at
night? Our research is focused on the daily regulation of sleep behavior using the fruit fly
Drosophila and incorporates a variety of approaches including biochemistry, molecular
biology, genetics, cell culture, electrophysiology, anatomy, and behavior.
Fly genetics has uncovered the molecular logic of circadian clocks that drive our
daily rhythms of sleep and wake. They consist of clock proteins that feed back and control
their own transcription. Remarkably, highly conserved clocks exist in humans. We are
interested in how these molecular networks develop. How does phosphorylation set the
speed of the clock? How do these feedback loops influence neuronal activity and output?
Astonishingly, fruit flies exhibit periods of inactivity with many of the cardinal
features of mammalian sleep, including homeostatic control and similar responses to drugs
such as caffeine. We have identified a fly sleep center in a region of the brain also
important in long-term memory known as the mushroom bodies (MB). We are interested in
understanding how the circadian clock and sleep loss influence the MB, how the MB
influence sleep, and what are the links between sleep and learning? Studies in the fly raise
the possibility of understanding the elusive function of sleep at the molecular level.
Thomas Bozza (2119 Pancoe)
My lab uses the olfactory system as a model to understand how genetically-defined
neuronal circuits develop, and how these circuits contribute to the representation of
sensory information in the brain. The olfactory system mediates the sense of smell. In
many animals, olfaction is critical for food location, predator avoidance, individual
recognition, as well as social and sexual behaviors that are crucial for the survival of the
species. As a model, the olfactory system provides powerful genetic tools to address
fundamental questions in neurobiology. The lab is currently studying how odorant receptor
genes influence the organization of inputs to the olfactory bulb of the brain, and how this
organization contributes to the processing of chemical information. To do this, we use a
variety of methods including mouse molecular genetics, optical imaging, and
electrophysiology
David Ferster (2139 Cook)
The mammalian visual cortex performs a remarkable transformation of the
information it receives from the eye. Neurons in the cortex are sensitive to the
orientation, motion, depth and size of objects in ways that the eye is not, which means the
cortex extracts this information from the nonspecific input it receives from the eye. We
are studying the neuronal mechanisms by which this cortex performs this transformation.
Neuronal connections are traced within the cortex and their functions observed during
normal vision by recording intracellularly from neurons in vivo using a patch recording
method developed in the lab. Our recent studies have focused on the manner in which
excitatory and inhibitory inputs interact, the mechanisms of oscillatory firing and the origin
of orientation and direction selectivity in cortical cells.
Jon Levine (Hogan 2-120)
My research interests are generally in the area of neuroendocrinology, which is the
study of the regulation of hormone secretions by the brain, and the regulation of brain
function by hormones. Our projects include studies of neurons that produce the
1
Faculty Laboratories Available for Undergraduate Research
neurohormone gonadotropin-releasing hormone (GnRH). Neurosecretion of GnRH mediates
the control of reproduction hormone secretions and fertility in both males and females, and
we are trying to understand how factors such as diet, season, stress, and age can alter
fertility by regulating gene expression and electrophysiological activity in GnRH neurons.
Many of our studies are also focused on the effects of steroid hormones - estrogen and
progesterone in females, and testosterone in males - regulate reproductive behaviors,
feeding, aggression, and parental responsiveness. To study the molecular and cellular
pathways by which these hormones alter these motivated behaviors, we use a variety of
physiological and molecular approaches in mice bearing null mutations of receptors or
signaling molecules, and in "gene knock-in" animals which express mutated receptors that
selectively activate certain signaling pathways. Our research is ultimately aimed towards
attaining a better understanding of certain forms of infertility, normal and aberrant
hormone-sensitive behaviors, and the effects of sex hormones on food intake and energy
homeostasis.
Mark Segraves (2137 Cook)
The long-term goal of my laboratory is to understand the neural basis of eye
movement planning, with a focus upon neuronal processing taking place within the cerebral
cortex and midbrain. These are higher brain centers involved in planning for movement.
Both humans and monkeys make series of rapid eye movements called saccades as they look
at an image or visual scene. It’s reasonable to assume that both human and monkey plan
ahead for several eye movements while viewing images and scenes but there is very little
empirical evidence to support this hypothesis. We would like to investigate the behavioral
and neural basis of this process in rhesus monkeys, and are approaching this by monitoring
neuron activity while monkeys make series of eye movements with conditions emulating the
search of a natural environment.
Fred Turek (2129 Cook)
Research in the Turek laboratory is focused on the study of sleep and circadian
rhythms, with special interest in identifying genes that regulate sleep and circadian
rhythms. Ongoing work on sleep and circadian rhythms includes an investigation of: (1) the
neurochemical, molecular, and cellular events involved in the entrainment, generation and
expression of circadian rhythms arising from a central biological clock located in the
suprachiasmatic nucleus (SCN) of the hypothalamus, (2) the genetics of the circadian clock
system and the molecular genetic mechanisms underlying the sleep-wake cycle, (3) the
feedback effects of the sleep-wake cycle on the circadian clock regulating the timing of
that cycle, (4) the effects of advanced age on the expression of behavioral and endocrine
rhythms, and on the expression of circadian clock genes, 5) the links between sleep,
circadian rhythms and energy metabolism and, (6) the role of melatonin in modulating sleep
and circadian rhythms.
In addition to our work on rodents, we have established extensive collaborations
with clinical researchers. Studies in humans are aimed at shifting the human clock in an
attempt to alleviate mental and physical problems that are associated with disorders in
circadian time keeping, particularly in the elderly and in shift-workers. In addition, we are
using both pharmacological and non-pharmacological approaches to determine if we can
reverse the effects of aging on the circadian clock system in both rodents and humans. Our
sleep, circadian and metabolic studies are focused on how disruption in these interactions
can lead to obesity, diabetes and CVD.
2
Faculty Laboratories Available for Undergraduate Research
Nelson Spruston (2409 Pancoe)
The Spruston lab studies the hippocampus, a region of the brain involved in learning
and memory. Our interest lies in understanding the properties of the various types of cells
and their functional properties and specializations that may underlie the cellular basis of
memory. Undergraduates typically participate in studies directed at understanding the
detailed structure or distribution of particular classes of neurons in the hippocampus.
These studies involve light and/or electron microscopy as well as immunocytochemical
studies.
Catherine Woolley
Research in the Woolley laboratory focuses on understanding how steroid hormones
influence the structure and function of brain circuits to alter behavior or induce pathology.
Currently, we are working on two NIH-funded projects. One is about estrogen-induced
changes in susceptibility to and severity of seizures related to epilepsy, and focuses on the
hippocampus. The other is about sex differences in drug addiction, and focuses on the
nucleus accumbens. Each project uses a multidisciplinary approach combining
electrophysiology, light and electron microscopic imaging, biochemistry, and behavior.
Biochemistry, Molecular Biology and Cell Biology
Rich Carthew (3111 Pancoe)
The cells in our bodies have specialized tasks, but must also fit together seamlessly
in tissues, adopting specific shapes to function properly. Our lab has discovered that
complex and beautiful tissue geometries can be explained by a fundamental principle of
physics. The observed shapes are accurately modeled by simply letting the tissue find the
configuration of least total energy. The major players in this process are the elastic
"stretchiness" of individual cells and the adhesive "stickiness" between cells. In this
manner, quantitative analysis of intricate tissue patterns is possible. Moreover, applying
this principle to tissue engineering could advance regenerative medicine.
Erv Goldberg (Hogan 4-100)
The Goldberg lab is interested in male reproduction, particularly in how sperm are
made and attain the ability to fertilize eggs. We do this work mainly with male mice and
study the proteins that appear during the process of spermatogenesis, especially the ones
that are unique to the testis. Undergraduates in my laboratory learn how to purify proteins,
mostly using recombinant technology, and how to study their function either as interactors
with other proteins of the testis or as enzymes involved in energy metabolism for sperm
motility. Biochemical and molecular procedures are taught in the lab. The results obtained
from our studies may have implications for developing male contraceptives or for curing
male infertility.
Jon Widom (4133 Cook)
Eukaryotic genomic DNA is wrapped into a repeating array of nucleosomes, which
occlude their wrapped DNA from interacting with many other gene regulatory proteins.
We have discovered that genomes care where along the DNA these nucleosomes are located
-- that is, genomes care which stretches of the DNA are wrapped in nucleosomes, and which
3
Faculty Laboratories Available for Undergraduate Research
are not. We showed further that genomes manifest this care by encoding an additional
layer of genetic information, superimposed on top of the regulatory and coding information
that were previously understood. We now have a good ability to read this genomic code for
nucleosome positioning, and to predict the in vivo locations of most nucleosomes. Now we
seek to understand the molecular basis of this encoding. We believe that it has to do with
the sequence-dependent mechanics of DNA itself. DNA in nucleosomes is exceptionally
sharply bent; sequences that bend especially easily will therefore be referred by
nucleosomes over sequences that bend less easily. A new project in the lab therefore seeks
to directly measure dynamic mechanical properties of DNA, such as its flexibility, from
static molecular images such as from atomic force microscopy and electron microscopy. Our
plan is to construct defined DNAs with sequences of special interest, image these by AFM
or EM, and the apply quantitative image analysis to extract desired the dynamic mechanical
properties. This work combined molecular biology experimental methods, nanoscale imaging,
and quantitative (computer-based) image analysis, and has the potential to revolutionize our
understanding of the relationship between DNA sequence and DNA function.
Jason Brickner (3105 Pancoe)
The current research in the Brickner lab centers on the importance of space and
time in cell biology. Specifically, we are studying how the nucleus is spatially organized and
how this spatial organization reflects the history of the cell. It has been recognized for
more than one hundred years that DNA within the nucleus is spatially organized. The
localization of a gene often reflects its expression. Historically, the nuclear periphery was
thought to be the place to which silenced regions of the genome are targeted. As a
postdoctoral fellow, professor Brickner discovered that certain genes relocalize from the
nucleoplasm to the periphery of the nucleus when they are activated in the yeast
Saccharomyces cerevisiae. It is now clear from the work of many labs that a large number
of genes exhibit similar behavior. The lab seeks to understand how gene localization is
controlled and the functional significance of localization in regulating transcription.
Kelly Mayo (Hogan 4-112)
Our laboratory investigates cell signaling and gene expression in the mammalian
reproductive axis. Our research program seeks to understand how hormones secreted from
the pituitary gland (FSH and LH) act on the ovary to bring about the changes in cell
proliferation, cell differentiation and gene expression that will result in ovulation and
luteinization of the ovarian follicle during each reproductive cycle. We use the genes
encoding the hormones inhibin and activin, which are produced in the ovary and act on the
pituitary gland to regulate reproductive hormone secretion, as a model system to address
these questions. We are presently focused on two major research directions. We are
investigating the dynamic regulation of inhibin expression during the reproductive cycle, and
are exploring the roles of cAMP-responsive transcription factors (CREB and ICER) as well
as the related orphan nuclear receptors steroidogenic factor-1 (SF-1) and liver receptor
homologue-1 (LRH-1), in this process. We are also investigating developmental pathways in
the ovary involved in the initial formation and growth of ovarian follicles, and are attempting
to understand how inhibin and activin regulate normal follicle development and how their
mis-expression might contribute to the formation of abnormal follicles. These studies also
investigate estrogen and Notch signaling in the early ovary, and examine ways in which these
pathways intersect with activin signaling. Our research focuses on molecular mechanism
4
Faculty Laboratories Available for Undergraduate Research
regulating normal reproductive function, but is substantially informed by, and relevant to,
reproductive disorders that impact fertility or result in infertility.
Ishwar Radhakrishnan (4135 Cook)
The Radhakrishnan lab is interested in understanding how eukaryotic gene
transcription is regulated at the molecular level. A variety of projects are in progress that
seek to clarify how transcription factors (i) recognize their DNA targets, (ii) set and
interpret the histone code, and (iii) collaborate with other factors to accomplish goals (i)
and (ii). A variety of biochemical, bioinformatics and biophysical approaches are employed
for these studies.
Andreas Matouschek (4105 Pancoe)
Our goal is to understand a complex cell biological process in the detail at which a
chemist understands an enzyme. We hope that a detailed understanding of this type would
lead to insights in the biology of this process that would not have been obtained otherwise.
We are particularly interested in processes in the cell during which proteins have to loose
their structure and unfold, and most recently, we have focused on protein degradation by
the proteasome. The proteasome is the major protease in the cytosol and nucleus of
eukaryotic cells and controls the concentrations of hundreds of regulatory proteins. It also
removes misfolded and damaged proteins from cells and produces some of the peptides that
are displayed on cell surfaces as part of the immune response. The proteasome itself is a
large protein machine, almost the size of the ribosome. Once it has recognized a substrate,
it unfolds the latter and, powered by ATP, runs along the substrate's polypeptide chain,
degrading it into small peptides.
There are two basic properties of the proteasome what we have investigated: first,
the proteasome is not expected to have any preferences for the amino acid sequence of its
substrates, because it any protein may end up damaged in the cell and therefore in need of
being disposed of; second, one would expect the proteasome to degrade its substrates
always completely into small pieces and not to produce larger fragments because these could
and would have unwanted biological activities. However, our studies have shown that there
appear to be important exceptions to both of these rules. We find that the proteasome has
quite pronounced sequence preferences and we are no exploring how these preferences can
protect some regulatory proteins from destruction but, unfortunately, also may allow some
dangerous proteins to escape detoxification and lead to disease such as in Huntington's
Disease. We also found a signal in some proteasome substrates that protects the part of
the polypeptide chain behind the signal from degradation. We think that this signal allows
the proteasome to fulfill a new role in the cell as a processing enzyme and that this
processing is an important part of some signaling pathways. A project in our lab would
involve protein engineering, biochemical assays, and cell culture work.
Carole LaBonne (3411 Pancoe)
The LaBonne laboratory works on the development of the neural crest, a stem cell
population that makes central contributions to the vertebrate body plan and has important
links to cancer. Investigating the role that specific regulatory factors play in neural crest
formation is key to understanding early vertebrate development and also lends important
insights into tumorigenesis. Neural crest cells undergo an epithelial-mesenchymal transition
(EMT) and migrates to distant regions of the embryo where they give rise to a diverse
array of derivatives. The mechanisms underlying the acquisition of migratory and invasive
5
Faculty Laboratories Available for Undergraduate Research
characteristics by neural crest cells have been co-opted by tumor cells, allowing them to
metastasize to distant site in the body and form secondary tumors. Key transcription
factors that regulate EMT in neural crest cells, including Snail, Slug, and Twist, also
regulate tumor cell metastasis and are proving to be valuable prognostic indicators for
metastatic tumors. Research projects in the LaBonne lab will center on using Xenopus and
zebrafish embryos, as well as tumor cell lines, to investigate how specific proteins
contribute to this process.
Thomas Meade (Tech L110)
Our lab’s research interests are focused in the area of the chemistry of life sciences
with an emphasis on coordination chemistry, bioinorganic chemistry, biological imaging and
the development of electronic biosensors. The specific topics of research and subgroups of
the lab include:
BIOLOGICAL MOLECULAR IMAGING: Design and synthesis of spectroscopic and magnetic
probes that incorporate novel functionality for magnetic resonance and fluorescence in vivo
microscopic imaging of biological systems with particular emphasis on nerve patterning,
regulation of cell lineage, gene expression and DNA transfection.
WEAK INTERACTIONS IN LIGAND-RECEPTOR BINDING: Using transition metal probes
to study long-range electronic coupling through stacked ¿-unsaturated systems, proteins
and the development of electronic DNA and protein biosensors.
METAL COMPLEXES AS ENZYME INHIBITORS: Investigate the interaction of smallmolecule transition metal complexes as enzyme inhibitors for the development of
therapeutic antitumor and antiviral drugs.
Erik Sontheimer (3137 Cook)
The Sontheimer Lab studies the roles of RNA molecules during gene expression,
with an emphasis on eukaryotic organisms. The primary focus is on the biochemical
mechanisms of RNA silencing pathways such as RNA interference (RNAi), in which small
RNA molecules direct the silencing of specific genes. We also study the biological roles and
molecular mechanisms of other noncoding RNAs such as microRNAs and natural antisense
RNAs.
Andrew Dudley (1411 Pancoe)
The evolution of higher organisms parallels the formation of increasingly complex
relationships between individual tissues. For example, the intricate motor skills of primates
depends on precise arrangement of dozens of tendons and muscles on a multi-component
articulated limb skeleton. The overall objective of our research is to define the molecular
and cellular mechanisms that determine tissue architecture with the goal of developing
novel approaches to enhance tissue regeneration. Our current studies use the chick and the
mouse limb as model systems for the developing skeleton. In particular, we are elucidating
how cell polarity regulates chondrocyte organization and thus determines the unique shapes
and growth properties of individual skeletal elements.
Alec Wang (1405 Pancoe)
The ultimate goal of stem cell research is to repair genetic defects in a patient
6
Faculty Laboratories Available for Undergraduate Research
genome, reprogram the patient cells into tissue-specific cells, enroute stem cells, and
transplant to repair the damaged tissue. To achieve this goal, reprogramming somatic cells
is one of the key steps. To reprogram somatic cells into stem cells, one must understand
what genes are essential for stem cells. Our research focuses on identifying novel genes
essential for the growth of embryonic stem cells. We have discovered a new family of
proteins implicated in microRNA pathway plays an essential role to maintain the survival and
growth of embryonic stem cells. We are currently examining a new way to reprogram
somatic cells by microRNAs.
Alfonso Mondragon (4131 Cook)
We are interested in the structure and function of proteins and nucleic acids. Two
areas of particular interest to us are: 1) nucleic acids and proteins that interact and modify
them, 2) flexibility and conformational changes in proteins. An example of our work on the
first subject is our study of the mechanism of type IA DNA topoisomerases. We have
solved the structure of both E. coli DNA topoisomerase I and III and their complexes with
nucleic acids. These structures have allowed us to propose a detailed mechanism of action
for this type of enzymes. We are also interested in the structure of large nucleic acids.
We are currently studying the structure of the RNA component of RNase P, a large
catalytic RNA molecule. The second area is exemplified by our studies of spectrin
flexibility. We solved four structures of tandem repeats of spectrin and used these
structures to propose atomic mechanisms to explain spectrin flexibility.
Rick Morimoto (3129 Cook)
Aging and stress, stress and aging — a pair of ominous human conditions that affect
quality of life. When events go awry, molecular events take place that, over time, can lead
to or enhance the risk of neurodegenerative disease. At the root of problem is a
fundamental process common to all cells, protein folding. When proteins misbehave and
misfold, they can adopt altered states that cause diseases of protein conformation including
the neurodegenerative diseases Huntington's disease, Amyotrophic Lateral Sclerosis,
Alzheimer's disease, Parkinson's disease, and Creutzfeld-Jacob. For each, a hallmark of
the disease is the appearance of misfolded and mutant proteins (Huntingtin, superoxide
dismutase, amyloid b peptide, a-synuclein) and associated toxicity. How these proteotoxic
species form, the processes that determine their persistence or clearance, and the
molecular basis of their toxicity are critical to understanding the disease mechanism. We
study how misfolded proteins cause cell stress and interfere with cellular function, the
identification and characterization of cellular machineries in protein homeostasis that
recognize and detoxify misfolded proteins, the basis of cell-type specific neurotoxicity, and
the identification of genes that regulate lifespan as a modulators of these events. The
identification of the chaperome network that determines protein quality control thus forms
the basis for a new class of therapeutics for neurodegenerative diseases of aging.
Robert Holmgren (3125 Cook)
The Holmgren lab studies signaling between cells. We are particularly interested in
the Hedgehog (Hh) pathway, which is conserved throughout most of the animal kingdom. In
humans, Hh is responsible for patterning the neural tube, appendages, and many organs. Our
research is focused on how Hh signaling leads to the translocation of the Ci/GLI
transcription factors into the nucleus and the subsequent activation of target genes. We
7
Faculty Laboratories Available for Undergraduate Research
study these questions in mammalian tissue culture and fruit flies using a variety of genetic,
molecular and cell biological approaches.
Eric Weiss (3413 Pancoe)
How does one cell become different from another? The process of cell fate
determination can be driven during cell division by asymmetric segregation of molecules or
structures that influence gene expression. Such segregation is intimately tied to the
underlying architecture of the cell and the timing of mitosis. We use the budding yeast S.
cerevisiae to understand how fundamental mechanisms of cell differentiation, the control of
cell morphology, and cell cycle regulation are coordinated. Our work largely centers on
protein kinase signaling cascades, and one of our key aims is to map the flow of information
through intracellular networks as comprehensively as possible.
Heather Pinkett (4129 Cook)
From bacteria to mammals, ATP-Binding Cassette (ABC) transporters are prevalent
everywhere there are cells. ABC transporters work as membrane bound molecular pumps to
import or export a broad spectrum of substrates, including proteins, sugars and toxins.
They use the binding and hydrolysis of ATP to power the transport substrates across
cellular membranes. To date, more than 50 human diseases are linked to defective
transporters, including cystic fibrosis. In the presence of ABC transporter multidrug
resistance protein 1 (MDR1), tumor cells are resistant to chemotoxic drugs, a particular
limitation to cancer chemotherapy. Deciphering the mechanism of transport, substrate
specificity and the role of ATP in substrate translocation is of great interest in the field.
The Pinkett lab is interested in understanding how this super family of proteins may use a
similar mechanism to transport select substrates into or out of the cell and the role
mutations play in reducing its ability to function as a transporter.
Greg Beitel (1407 Pancoe)
Claudin-family proteins are small four trans-membrane domain proteins that are
integral parts of the junctional complexes that prevent fluid and ion passage between cells.
These “paracellular barriers” are important in epithelial tissues to separate internal organs
from the outside environment (e.g. prevent acid stomach contents from leaking into the
blood stream) and in endothelial cells and glia to create the blood/brain barrier that
protects the nervous system from pathogens and potentially dangerous chemicals. Although
claudins have been shown to play central roles in the barrier, the functions of the different
parts of claudin molecules are poorly understood. In Drosophila, two related claudin
molecules, Sinuous and Megatrachea, are both required to for barrier junction formation.
That they are both required indicates that they have distinct functions. To identify the
parts of these proteins that confer the distinct functions, we are making a series of
chimeras (domain swaps) between the two proteins. Using transgenic animals, genetic
crosses and immunohistochemical assays, we will investigate the in vivo function of the
chimeric proteins. Once regions that harbor specific functions have been identified, we
would work to identify proteins that interact with those regions.
Amy Rosenzweig (4137 Cook)
The goal of our research program is to understand metalloprotein function on the
molecular level by using X-ray crystallographic, biophysical, and biochemical techniques.
8
Faculty Laboratories Available for Undergraduate Research
Projects in the laboratory are divided into two areas, metalloenzymes and metal trafficking
proteins, with an increasing focus on structural characterization of integral membrane
proteins. We recently determined the molecular structure of Nature’s predominant methane
oxidation catalyst, a metalloenzyme called particulate methane monooxygenase (pMMO).
pMMO converts methane, the most inert hydrocarbon, to methanol. We have also
determined structures of metallochaperones involved in copper delivery to Cu +-ATPases and
to cytochrome c oxidase. Mutations in Cu+-ATPases, which are integral membrane proteins
that couple the energy of ATP hydrolysis to Cu+ translocation across membranes, are linked
to Wilson disease and Menkes syndrome.
Other Departments
Joe Bass (4405 Pancoe)
The major focus of research in the Bass laboratory is on the molecular links
between neural circuits coordinating sleep, wakefulness and feeding behavior, with systems
important in peripheral fuel utilization, including the insulin-signaling pathway. Two
overarching themes in our research are: (1) Transcriptional and posttranslational
interactions between circadian and metabolic gene networks in the development of diabetes
and obesity: We discovered that mutation of the gene encoding the transcription factor
CLOCK, present within both brain and in peripheral metabolic tissues, leads to altered sleep,
feeding activity, obesity and diabetes (Science 2005). These studies prompted us to search
for targets of the Clock gene network within appetite centers of the brain and within
peripheral tissues involved in lipid and carbohydrate utilization. Our work led to the
surprising observation that mutation of the Clock gene disrupts hypothalamic expression of
the wakefulness peptide hypocretin/orexin and appetite-suppressing neuropeptide
melanocyte-stimulating hormone. Projects in the laboratory now exploit both genetic and
biochemical methods to pinpoint the cell and molecular basis for co-regulation of circadian,
sleep and metabolic pathways within specific cells of hypothalamus, and peripheral metabolic
tissues. (2) Genetic and genomic analysis of glucose metabolism and insulin resistance: We
have developed genetic and genomic tools to evaluate targets involved in the regulation of
body weight, glucose and lipid metabolism in vertebrates. We have used “reverse” gene
targeting to create new diabetes “knock-in” mice in which human mutations have been
introduced into the mouse genome. The new humanized diabetic mice that we have
generated reconstitute the human disease but also lead to profound defects in the
regulation of sleep, activity and feeding. These studies are conducted in parallel with
analyses of factors regulating cell and molecular control of insulin receptor signaling within
brain and peripheral metabolic tissues including liver, pancreas, fat and muscle. Gene knockin and cell-based platforms provide new approaches to correlating genotype with phenotype
in human insulin resistance syndromes. Understanding the pathways that link circadian
activity, sleep, feeding and metabolic homeostasis, and delineating the impact of changes in
each parameter on the whole organism, will hopefully bring us one step closer to a unified
“systems” map of metabolic disease.
Kurt Horvath (4401 Pancoe)
My lab studies mammalian antiviral responses and the strategies that some viruses
have evolved to evade them. Diverse projects are underway, exploring the molecular basis
for virus detection, the cytokine signal transduction apparatus leading to virus-induced host
gene expression, and the biological activities of the antiviral effects of the protein
9
Faculty Laboratories Available for Undergraduate Research
products. In parallel, the unique capacity of RNA viruses to disengage these host immune
responses is being dissected at the molecular and biochemical level.
Hans-Georg Simon (Childrens Hospital; [email protected])
Building and re-building of limbs and hearts. The Simon Laboratory has identified
regulatory genes that play key roles in limb development in virtually all vertebrates,
including humans. Surprisingly, these genes are also critical for the shaping of the heart
during embryogenesis and when mutated in humans, they lead to birth defects of the arms
and heart. Using zebrafish, chicken, and mouse models, the lab tries to gain a deeper
understanding of common genetic pathways in limb and heart development and disease. In
addition to these developmental studies, the lab is interested in discovering the genes that
are involved in regenerative processes. As models for these investigations, zebrafish and
newts are employed, which can regenerate limbs and heart ventricles throughout their life
times. The identification of genetic pathways that are operational in these regenerating
species but not in mammals, will provide new insights how to restore regenerative abilities in
non-regenerating species including humans.
10