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Examples of UAB IDDRC Research by Project Leaders

Mark Bevensee
The Bevensee laboratory is interested in the cellular and molecular physiology of intracellular pH (pHi) regulation and acid-base transport in tissues such as brain and heart. Changes in cell and/or tissue pH can influence important processes such as enzyme activity and neuronal firing. To regulate pHi, cells have evolved mechanisms such as membrane transporters to move acids (e.g., H+) or bases (e.g., bicarbonate or HCO3) across their plasma membranes. Some of these proteins include Na-H exchangers, Na/HCO3 cotransporters, and Na-dependent and -independent Cl-HCO3 exchangers. Much is unknown about the function, regulation, and molecular identities of these and other acid-base transport mechanisms. In our cellular studies, we use fluorescence imaging and patch-clamp techniques to identify and characterize the function of pHi-regulating mechanisms in mammalian neurons and glia. Studies include evaluating ion dependencies, inhibitors, and pH- and voltage-dependencies of transport proteins. They are also interested in the effects of neuromodulators and cell-volume perturbations on pHi regulation and the correlation between pH1 changes and neuronal firing. In another area of research, the laboratory is elucidating the molecular nature of Na/HCO3 cotransporters (NBCs) and other members of the bicarbonate-transporter superfamily. Many NBC-related proteins are present in brain and heart. The laboratory is identifying the cDNAs that encode bicarbonate transporters, and subsequently characterizing the structure-function relationships and regulation of the proteins expressed in either frog oocytes impaled with microelectrodes, or transfected mammalian cells loaded with ion-sensitive dyes. The combined results from cellular and molecular studies will enhance our understanding of both the physiology of pHi regulation and the biophysics of bicarbonate transport.

Gautam Bijur
The Bijur laboratory examines the role of glycogen synthase kinase-3beta (GSK3b) as a key component in numerous cell signaling cascades, affecting many fundamental cellular functions associated with neural plasticity. For example, GSK3b is being recognized as an important mediator of apoptosis, a process of cell death that may contribute to neuronal loss following brain injury due to cerebral ischemia and in certain types of neurodegenerative diseases. The selective activation of GSK3b in the nuclear and mitochondrial compartments is likely a major factor in the proapoptotic actions of GSK3b. These studies will examine whether nuclear GSK plays a role in apoptosis, test the effects of modulating nuclear GSK3b on two transcription factors, cAMP response element binding protein (CREB) and heat shock factor-1 (HSF1), which are critical for maintaining neural plasticity and cell survival, and selectively modulate the activity of mitochondrial GSK3b to determine whether increased mitochondria GSK3b contributes to apoptotic signaling. If GSK3b plays a deleterious role in the generation of neuronal damage following NMDA treatment and in a model of transient focal cerebral ischemia, and if inhibition of GSK3b has the potential to provide significant therapeutic neuronal protection from both insults, these studies will identify the mechanisms by which GSK3b activity is regulated and suggest treatment strategies for disorders such as brain ischemia and neurodegenerative disease.

Rita Cowell
The Cowell laboratory is examining the involvement of peroxisome proliferator activated receptor g (PPARg) coactivator 1a (PGC-1a) in the metabolic homeostasis of inhibitory neurons. Experiments are designed to test the hypotheses that 1) PGC-1a regulates metabolism and synaptic plasticity in GABAergic neurons in vitro and in vivo, 2) adverse perinatal events (hypoxia) have a long-term effect on the maturation of GABAergic circuits by disrupting normal PGC-1a expression and histone acetylation in development, and 3) the expression levels of PGC-1a and related metabolic genes are altered in inhibitory interneurons in the cortex of schizophrenic patients. The laboratory utilizes cell culture, rodent models of perinatal hypoxia, assessment of chromatin acetylation/methylation status, and laser capture microdissection from human postmortem brain tissue in order to elucidate the mechanisms by which disturbances in brain development contribute to the pathogenesis of schizophrenia, an important developmental disability of affect and interpersonal interactions.

Lynn Dobrunz
Electrophysiological approaches to study synaptic transmission and regulation of presynaptic properties at synapses in the central nervous system. Synapses in the central nervous system are unreliable in that they release a vesicle of neurotransmitter only a small fraction of the time they receive action potential input. The probability of neurotransmitter release is history dependent, resulting in dynamic modulation of synaptic strength by the timing of stimulation, a phenomenon called short-term plasticity. Short-term plasticity is important for information processing in the brain. In hippocampus, a region of the brain involved in learning and memory, short-term plasticity is a cellular correlate of short-term memory. Using hippocampal brain slices and cultured hippocampal neurons from rodents, presynaptic properties of single synapses and the regulation of presynaptic vesicle release probability is evaluated. Projects include: the effects of developmental regulation on presynaptic function in neonatal hippocampus; differences in presynaptic properties of excitatory synapses onto excitatory cells vs. inhibitory cells in hippocampus; and synaptogenesis and the physiological properties of newly formed synapses in cultured hippocampal neurons.

Paul Gamlin
The Gamlin laboratory is examining the role of intrinsically-photoreceptive retinal ganglion cells in pupillary responses and entrainment of circadian rhythms. Compelling evidence exists that ganglion cells in primate retina project to the ON and lateral geniculate nucleus, and contribute significantly to pupillary responses. The goals of the proposed studies in primates are therefore to: 1) characterize these intrinsically-photoreceptive ganglion cells; 2) investigate their influence on the visual physiology of PON neurons; 3) examine their hypothesized projections to the SCN; 4) determine their influence on the visual physiology of SCN neurons; and 5) determine their contribution to pupillary responses in the primate. These are important research questions, since the circadian system regulates such physiologically important behaviors as activity, body temperature, and sleep/wake cycles, and the pupillary light reflex is a clinically important diagnostic tool. If, as preliminary data indicates, pupillary responses are influenced throughout much of the photopic range by inputs from intrinsically photoreceptive ganglion cells, this has important consequences for our understanding the pupillary light reflex and for its clinical evaluation. Also, if the same retinal ganglion cells project to both SCN and PON, then it will be possible to extrapolate from information that is readily derived in the pupillary system to the circadian system, where entrainment experiments take longer. Finally, beside their roles in pupil control and circadian rhythms, these ganglion cells project to the lateral geniculate nucleus and are likely to have very broad-reaching effect on other human visual behaviors.

John Hablitz
Studies of synaptic transmission are designed to explore basic biophysical properties of mammalian central neurons, as well as to explore the pathophysiology of experimental epilepsy. Electrophysiological techniques, including whole-cell voltage-clamp recordings from visually identified neurons, are used in vitro brain slice preparations. The goal of these studies is to determine the types of synaptic interactions present among pyramidal cells and interneurons in neocortex and how these patterns change during development. Additional studies involve the use of optical recording techniques and voltage-sensitive dyes and studies using animal models of cortical heterotopia to produce neonatal epilepsy. These studies examine the spatial and temporal extent of cortical circuit activation in normal neocortex and utilize an animal model of cortical dysplasia.