Faculty
are listed by Department within their Research Areas,
with descriptions of their active projects.
DEPARTMENT OF PHARMACOLOGY
DAVID H. FARB
Professor and Chairman of Pharmacology; PhD, Brandeis University
Research Interests: Abnormal activation of amino acid receptors has been implicated
in the etiology of psychiatric disorders such as anxiety, depression,
and schizophrenia, as well as of seizure disorders. Ongoing studies
in the Farb lab provide a strong foundation for constructing models
of steroid hormone interactions with excitatory and inhibitory amino
acid receptors in the brain and spinal cord. This knowledge may
lead to new strategies for the treatment of psychiatric and cognitive
disorders. Although there is widespread medical and nonmedical use
(and abuse) of steroids, there is very little information concerning
the long-term effects of steroid exposure on the central nervous
system. Rational drug design in conjunction with structural computational
chemistry will be used to understand ligand receptor and DNA transcription
factor recognition.
Dr. Farb's lab studies focuses on the mechanism
of action of neuromodulators and on the structure, function, and
cellular dynamics of amino acid receptors in the brain and spinal
cord. Amino acid receptor function can be controlled by direct modulation
of receptor function on the time scale of milliseconds to seconds
and by regulation of receptor expression by genomic mechanisms.
The role of neuroactive steroids in the control of GABA, glycine,
and glutamate (NMDA and non-NMDA) receptors is being investigated
using a multidisciplinary approach that includes the techniques
of molecular biology, patch-clamp neurophysiology, cell biology,
and molecular neuroanatomy. We have isolated segments of DNA from
the human genome that contain the genetic blueprint for the production
of GABA receptors. By determining the sequences for the regions
of the gene that control its expression, we hope to be able to identify
receptor-specific transcription factors and to design new classes
of therapeutic agents that may act by regulating the expression
of neurotransmitter receptors in the brain.
TERRELL T. GIBBS
Assistant Professor; PhD, Harvard Medical School
Research Interests: Dr. Gibbs' research efforts focus on the pharmacology of neurotransmitters
and neuromodulators, and on mechanisms of modulation and regulation
of neurotransmitter receptor function, including up-regulation,
down-regulation, desensitization, and tolerance. Current studies
concern the acute and chronic effects of modulators of amino acid
receptor function, including benzodiazepines, barbiturates, and
steroids. Computational methods are used to evaluate thermodynamically
plausible models for receptor function. Trainees will be involved
in the design and execution of pharmacological experiments, and
will be trained in the use of radioligand and/or electrophysiological
techniques of studying receptor function.
SUSAN E. LEEMAN
Professor; PhD, Radcliffe College
Research Interests: Work continues to focus on the two peptides, substance P (SP) and
neurotensin, that were isolated and chemically defined in this laboratory.
Projects that are currently underway relating to the biochemistry
and pharmacology of SP include studies to determine the binding
domains of SP with its receptor using photoactivatable derivatives
of SP containing the photoreactive amino acid benzoylphenylalanine;
to determine the binding domains of an antagonist of SP, CP 96,345
using a photoactivatable derivative of this compound; the role of
SP in inflammatory processes in the gastrointestinal tract using
non-peptide SP antagonists to inhibit intestinal responses to Clostridium
difficile Toxin A; the characterization of calcium signals generated
by administration of SP to CHO cells transfected with mRNA encoding
the full-length SP receptor and a truncated form of the SP receptor
missing the C-terminal cytoplasmic tail; the effects of stress on
the SP responsive functional properties of peritoneal macrophages
elicited by thioglycolate administration. A new project is the development
of a diphtheria toxin related SP-fusion protein that is cytotoxic
for cells expressing SP receptors.
Projects relating to neurotensin in the CNS
focus mainly on the participation of neurotensin in the central
nervous system regulation of LH secretion. A study on the effect
of estrogen on the decreasing abundance of mRNA encoding the neurotensin
receptor in the suprachiasmatic nucleus of female rats is in progress.
In addition, a project has been initiated to study the interactions
of NT and corticotropin-releasing factor (CRF) on responses of the
intestine and colon to immobilization stress in rats.
ISABELLE M. MINTZ
Assistant Professor; PhD, University of Paris VI (France)
Research Interests: Although it is generally appreciated that Ca channels play crucial
roles in the shaping of action potentials and firing patterns, as
well as in control of transmitter release at nerve terminals, the
study of these roles has been limited by the availability of selective
tools for blocking Ca channels. The recent isolation of w-Aga-IVA
(from spider venom) constitutes a significant advance since this
toxin may be used to target a unique population of Ca channels whose
roles were difficult to discriminate previously.
Students supported by this training grant will
join the PI's effort to pursue the following studies: 1) patch-clamp
recordings from tissue slices or freshly dissociated neurons to
investigate whether the toxin w-Aga-IVA blocks more than one population
of Ca channels (as suggested recently by R. W. Tsien and collaborators);
2) photometric studies of presynaptic Ca transients to determine
the regulation of synaptic strength by transmitters that affect
presynaptic Ca channels differentially; and 3) patch-clamp recordings
of Purkinje neurons in combination with photometric measurements
of Ca to study the link between P-type Ca channels and internal
Ca release, and how each contributes to the processing of synaptic
inputs.
Since Ca channels sensitive to w-Aga-IVA are
ubiquitous in the CNS, there is no question that these studies will
provide greater insight into the many cellular functions controlled
by Ca (e.g., promotion of neuronal growth, regulation of genes and
enzymes, etc.) as well as into the pathological situations which
arise when Ca homeostatic mechanisms are disrupted, as is thought
to occur with epilepsy, excitotoxicity, and neuronal death.
SHELLEY J. RUSSEK
Professor; PhD, Boston University Medical School
Research Interests:The identification of gene families with multiple genes that code
for related yet distinct receptor isoforms has added a rhttp://www.bu.edu/psych/faculty/hasselmo/emarkable
increase to the level of specificity and complexity that may govern
the regulation of neurotransmitter receptors in the CNS. For instance,
the diverse set of genes coding for GABAA receptors constitutes
a gene family that displays an unusual degree of differential developmental
and cell-specific expression. By controlling the number and kind
of GABAA receptors present at synaptic and extrasynaptic sites,
individual neurons have the capacity to respond dynamically to alterations
in membrane excitability. A major component of this cellular response
may be the switching on and off of receptor subunit specific genes
through the activation of second messenger systems. To understand
the relationship between receptor activation and receptor specific
gene expression, they have focused our efforts on identifying the
factors that promote and inhibit the transcription of GABAA receptor
genes. By transfecting luciferase reporter constructs into primary
neocortical and hippocampal cultures, we have identified the activity
of a promoter that is downregulated by chronic activation of GABAA
receptors. Using information about the functional binding sites
for important DNA/protein interactions, Dr. Russek hopes to understand
the rules that govern autologous regulation of GABAA receptor genes
and cell specific transcription in the CNS. She is also interested
in the evolution of amino acid receptor heterogeneity and has determined
that the majority of human GABAA receptor subunit genes evolved
from the duplication and translocation of an original a-a-b-g gene
cluster. Efforts have been made to use microdissected chromosomal
DNA to localize specific genes to the human chromosomes and to identify
new amino acid receptor gene clusters that may be distributed in
the genome.
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