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Center
for Epithelial Function in Health and Disease
Dr. Walter Boron’s laboratory studies the ion-transport
processes involved in regulation of intracellular pH (pHi), and how
these transporters are themselves regulated by cell volume, hormones,
and oncogenes. A variety of pH-sensitive microelectrodes and dyes
(including digital imaging techniques) are used to monitor pHi in single
cells (e.g., neurons, glia, muscle, mesangial cells, osteoclasts, and
cells of perfused renal tubules, gastric glands and colonic crypts). The
primary objective is to deduce mechanisms by which acids and bases are
transported across membranes, how the transporters are regulated, and
how pHi changes affect processes such as growth control, transepithelial
acid-base transport, and the tone of vascular smooth muscle. The
laboratory is also attempting to clone the genes for bicarbonate
transport proteins. Dr. Robert Bridges' primary area of research is on epithelial ion transport with a special focus on epithelial ion channels. His lab uses a wide range of electrophysiological methods and video imaging to study the regulation, pharmacology and biophysics of ion channels including CFTR, ENaC and various potassium channels. He collaborates with several pharmaceutical companies working toward the development of drugs for the treatment of Cystic Fibrosis and Chronic Obstructive Pulmonary Disease. Dr. Eric Delpire’s research topics include the physiology of electroneutral cation-chloride cotransporters, regulation of intracellular chloride in neurons and GABAergic neurotransmission. GABAergic neurotransmission depends upon the transmembrane Cl concentration gradient that exists at the synapse. The intracellular Cl concentration in CNS and PNS neurons is regulated, in part, by cation-chloride cotransport mechanisms such as Na-K-2Cl and K-Cl cotransporters. For example, the inward Na-K-2Cl cotransporter is highly expressed in immature CNS neurons, resulting in a high intracellular Cl- concentration and GABA depolarizing or excitatory responses. In contrast, mature CNS neurons have low Na-K-2Cl cotransporter and high K-Cl cotransporter activity, leading to low intracellular Cl- and hyperpolarizing or inhibitory GABA responses. His laboratory is creating knockouts of the cotransporters and studying their relationship with neurotransmission and behavior. His work, in collaboration with Drs. Robert MacDonald and Mike McDonald, involves molecular biology, physiology, electrophysiology and behavior. These studies have significance in perception of pain, hyper-excitability and epilepsy, nerve conduction, peripheral neuropathy and paraplegia. Dr. Shmuel Muallem's research involves regulation of fluid and electrolyte secretion by epithelial cells. A key protein regulating epithelial function is the Cystic Fibrosis Transmembrane Regulator (CFTR). Dr. Muallem's work is geared towards understanding how CFTR regulates the activity of other transport proteins, in particular HCO3- transport across the luminal membrane. He believes that defective regulation of HCO3- transport is a critical problem in Cystic Fibrosis patients. Another aspect of his work is the study of the function of Ca2+ transport and signaling proteins and their organization into complexes. Electrophysiological and confocal imaging techniques are used to monitor Ca2+ in subcellular compartments and follow the activity of Ca2+ pumps and Ca2+ channels. These approaches are complemented by a variety of biochemical and molecular techniques to study the organization of Ca2+ signaling complexes in microdomains of polarized cells.
Dr. Hanno Steen is a pioneer in developing methods
for the qualitative and quantitative analysis of protein modifications
of complex protein mixtures by mass spectrometry, with special emphasis
on tyrosine phosphorylation. In carcinogenesis, the pivotal role of
tyrosine phosphorylation is underscored by the notion that almost half
of the oncogenes known to date encode tyrosine kinases.
External Advisory Committee (2002 - 2007)
The external advisors are not only established investigators with
expertise appropriate for the junior faculty, but also leaders in the
discipline of epithelial physiology recognized for their achievements by
receipt of international awards, journal editorships, and elected office
in scientific societies and organizations. Junior faculty participants of
this COBRE benefit greatly from mentoring and evaluation by these
renowned scientists.
Dr. Alper is a Professor of Medicine at Beth-Israel Deaconess Medical
Center, Harvard University. The Alper laboratory studies the molecular
basis of transmembrane and transepithelial ion transport, with foci on
the ion exchange, ion co-transport, and channel mediated conductive
transport of chloride, bicarbonate, and potassium. The laboratory is
recognized for cloning variant transcripts from each of the three genes
of the band-3 anion exchanger family. The physiological role of these
polypeptides is being evaluated in intact animals subject to
perturbations of acid-base status and extra-cellular fluid volume.
Ongoing work also addresses the molecular pharmacology of K+ channel
targets in sickle cell disease, secretory diarrhea, and polycystic
kidney disease. Dr. Beyenbach is a Professor of Physiology in the Department of
Biomedical Sciences, College of Veterinary Medicine, Cornell University.
Dr. Beyenbach’s laboratory studies the mechanisms and regulation of
epithelial transport, and significant aspects of renal function such as
aglomerular urine formation, transport across insect malpighian tubules,
and mechanisms of magnesium homeostasis. Dr. Beyenbach and his research
group are adept at the use of sophisticated electrophysiological
techniques to define transport pathways in micro-preparations. The
laboratory is internationally recognized for their work defining novel
ion transport and fluid secretion mechanisms.
Dr. Boron is a Professor of Cellular and Molecular Physiology at Yale
University. His laboratory studies the ion-transport processes involved
in regulation of intracellular pH (pHi), and how these transporters are
themselves regulated by cell volume, hormones, and oncogenes. A variety
of pH-sensitive microelectrodes and dyes (including digital imaging
techniques) are used to monitor pHi in single cells (e.g., neurons, glia,
muscle, mesangial cells, osteoclasts, and cells of perfused renal
tubules, gastric glands and colonic crypts). The primary objective is to
deduce mechanisms by which acids and bases are transported across
membranes, how the transporters are regulated, and how pHi changes
affect processes such as growth control, transepithelial acid-base
transport, and the tone of vascular smooth muscle. The laboratory is
also attempting to clone the genes for bicarbonate transport proteins. Dr. Brown is a Professor of Medicine at Massachusetts General Hospital,
Harvard University, as well as the Editor-in-Chief of the
American Journal of Physiology
(Cell Physiology). Dr. Brown’s
laboratory investigates the establishment and maintenance of the
polarized distribution of transport proteins in the apical and/or
basolateral plasma membranes of epithelial cells, with an emphasis on
roles of cytoskeleton and GTP-binding proteins in vesicle transport and
membrane recycling. The work is specifically relevant to renal function
and of general significance to epithelial cell biology.
Dr. Dawson is a Professor and Chair of Physiology & Pharmacology at
Oregon Health Sciences University. Research in Dr. Dawson’s laboratory
is aimed at understanding the structural basis for the conduction and
gating properties of ion selective channels, particularly CFTR.
Molecular biological and electrophysiological techniques are being used
to investigate the role of different protein domains in normal and
abnormal channel gating. The long term goals are to engineer novel forms
of CFTR for use in gene therapy, and to design blockers of the channel
useful for treatment of secretory diarrhea. Dr. Wills is a Professor in the Department of Physiology and Biophysics at the University of Texas, Medical Branch (UTMB). Dr. Wills’ laboratory is engaged in structure-function studies of epithelial ion channels. The Wills laboratory recently cloned several members of the ClC-family of voltage-gated chloride channels from a cultured renal epithelial cell line (A6) and human retinal pigment epithelial cells. The long term goal of the laboratory is identification of factors that modulate epithelial ion channel expression and gating.
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