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Name, Field, Position, Department, and Keyword |
 
Faculty Keywords: Cell and Molecular Neuroscience (23), Hippocampus (11), Mouse (11), Neurotransmitter receptors and transporters (9) The solution of seeming impossible experimental problems drives our creation of new experimental technologies for neuroscience, which during the past thirty years have focused primarily on observing the dynamics of the biomolecular processes of life. This challenge requires benign, effectively non-invasive methods that frequently push the physical limits of resolution in space, time and sensitivity. Several of these innovations: Multiphoton Microscopy (MPM), Fluorescence Correlation Spectroscopy (FCS), nanoscopic molecular tracking and most recently, nanostructured molecular dynamic probes are being applied to some of these seeming impossible biological problems. Over the years, about 35 of our publications have focused on the challenges of neuroscience, including: molecular mechanisms and physics of auditory transduction, the first successful single channel recording of reconstituted natural ion channels and on their structural fluctuations and mechano-sensitivity, signal delays along neural processes in neural networks, detection and imaging of serotonin and its secretion, imaging the development of the lesions of AlzheimerÌs Disease in transgenic mice, and most recently (now in press) successful optical imaging of action potentials with time resolutions corresponding to patch clamp recordings which promises to supplement the usual application of MPM to calcium signals as a method of choice for neural response measurements in live neural networks. |
Faculty Keywords: caged neurotransmitters (1), Cell and Molecular Neuroscience (23), Ion channel (6), Ligand-activated ion channels (2), Neurotransmitter receptors and transporters (9), Patch clamp (2) We are investigating the structure and function of membrane-bound proteins (neurotransmitter receptors) that control and integrate communication between the cells of the nervous system. Malfunction of the receptors is implicated in many diseases of the nervous system, and the receptor proteins are the targets of a large class of clinically important compounds and abused drugs. Until recently investigation of the mechanism of action of these receptor proteins has been hampered by the lack of techniques with adequate time resolution (microseconds-to-milliseconds). My group has developed new biophysical techniques, most recently a laser-pulse photolysis method using caged neruotranmsitters, for investigating the receptors in cells isolated from specific areas of the nervous system to fill this gap. When a neurotransmitter binds to the active receptor forms, ion-conducting receptor-channels open, initiating electrical signals that transmit information in the nervous system. Whether or not a signal is transmitted depends on the concentration of open receptor-channels. This in turn depends on the neurotransmitter concentration and the length of time receptors are exposed to it. The immediate goal is to determine quantitative models, on a physiologically relevant time scale, for the chemical kinetic reactions of excitatory and inhibitory neurotransmitter [acetylcholine, gamma-aminobutyric acid, (GABA), glycine, glutamate, N-methyl-D-aspartate (NMDA) and serotonin receptors]. This goal has already been achieved with the nicotinic acetylcholine receptor from the electric organ (modified muscle) of certain fish. The eventual aim is to integrate all the available information into a consistent mechanism of signal transmission in the mammalian central nervous system. The chemical mechanism of neurotransmitter receptor-mediated reactions is expected to set limits to the various hypotheses concerning the operation of neuronal circuits and brain function, and to lead to an understanding of the effects of pharmacological agents and abused drugs on receptor function. An interdisciplinary approach, involving physical and organic chemistry, instrument development, molecular biology, electrophysiology, cellular neurobiology, and computer simulation, is being used to achieve these aims. |
Faculty associated with: Anna E. Beaudin Keywords: Cell and Molecular Neuroscience (23), Development (21), Genetics (9) Numerous genetic and nutritional epidemiological studies have demonstrated an association between impaired folate metabolism and risk for certain developmental anomalies including neural tube defects (NTDs). These disorders are common and potentially preventable in all human populations, however little is known about the biochemical mechanisms that regulate folate metabolism, or the role of altered folate metabolism in the initiation or progression of these disorders. The Stover laboratory focus on understanding how impairments in the metabolism of folic acid and other B-vitamins, due to nutritional deficiencies or genetic variations, alter DNA stability and expression, and how these alterations in DNA function cause disease and developmental anomalies. Folate-dependent one-carbon metabolism is required for the synthesis of purines, thymidylate and S-adenosylmethionine. Impairments in folate metabolism result from nutritional deficiencies or common and highly penetrant single nucleotide polymorphisms and increase risk for birth effects. Impairments in folate metabolism affect genome integrity, and the regulation of about 10% of mammalian genes whose transcription is regulated by cytosine and histone methylation. The Stover laboratory has recently identified new pathways for the regulation of folate metabolism and folate accumulation and the regulation of cellular methylation reactions. We have generated a number of gain-of-function and loss-of-function murine model systems to study folate metabolism during development. These model systems are used to quantify the effects of altered folate metabolism on genomic outcomes including methylation, transcription, mutation rates, and pathologic outcomes including neural tube defects and cancer. The laboratory employs a number of experimental techniques including stable isotope metabolic tracer studies to quantify metabolic flux, mass spectrometry to quantify genome integrity (uracil and methylcytosine content), and expression profiling using cDNA and oligonucleotide microarrays. These approaches, integrated with standard molecular biology and biochemical techniques, enable us to investigate the regulation of folate metabolism and comprehensively address the interactions among metabolic and genomic pathways in human health and disease. |
Please report corrections, questions, comments, and problems to: Lori Miller (lmm8 AT cornell.edu)