Research

Neuroscience Research Group

 

Dr. RICHARD m. COSTANZO

Dr. Richard M. Costanzo and his research group focuses on the unique capacity of the olfactory system to undergo neurogenesis and replace degenerating neurons. They have shown that newly replaced olfactory neurons are capable of reestablishing functional connections with their target cells and to “rewire the brain.” Using anatomical, molecular, electrophysiological and behavioral techniques, Dr. Costanzo’s group is investigating the survival characteristics of the olfactory stem cells when transplanted into different regions of the brain.

Dr. LOUIS J. DE FELICE


A fluorescent probe (ASP+) in transit through the human serotonin transporter.

Dr. Louis J. De Felice and his laboratory focus on serotonin (5HT), dopamine (DA), and norepinephrine (NE) transporters. Serotonin transporters (SERTs), dopamine transporters (DATs), and NE transporters (NETs) are integral membrane proteins. Drugs, such as cocaine and antidepressants, act on neurotransmitter transporters and amphetamines and methamphetamines are taken up by neurons through these transporters, underlining the importance of these molecules on human behavior. Using cloned transporters transfected into host cells and native neuronal cells in tissue culture, De Felice and his group measure the ionic currents accompanying transport using two-microelectrode voltage clamp in frog oocytes and patch-clamp techniques on single mammalian cells. Cell-detached patches allow the lab to examine the kinetics of individual transporters, analogous to the study of single ion channels, and to study the regulation of transporters by ancillary proteins and small molecules. This information, in combination with classical radio-labeled uptake, amperometry, cell surface markers and correlative structural studies provide a comprehensive approach to the structure and function of neurotransmitter transporters.

Dr. JAVIER GONZALEZ-MAESO

The goal of research in the laboratory of Dr. Gonzalez-Maeso is to explore the structure, function and regulation of G protein-coupled receptors (GPCRs), translating this basic knowledge into novel strategies to treat psychiatric disorders such as schizophrenia, suicide and alcoholism. His group has also a great interest in understanding the molecular and cellular mechanisms by which environmental factors and chronic drug exposure alter behavioral phenotypes in mouse models. The research is based on the combination of interdisciplinary approaches ranging from computer structural modeling and molecular pharmacology in tissue culture to neurochemistry, epigenetics, mouse behavioral assays relevant to psychiatric disorders, and functional testing in postmortem human brain samples.

Dr. JOHN GRIDER

The group led by Dr. John Grider focuses on the examination of the enteric nervous system in human and animal models with the goal of identifying the neural circuit which regulates intestinal smooth muscle motility, and the changes in neuronal phenotype and circuitry that occur during development and in response to inflammation. The intimate relationships between nerve and muscle are evaluated by a variety of histochemical, molecular, and biochemical techniques. Intact preparations that retain the in situ interconnections are used to examine circuits; isolated and cultured enteric neurons are used to examine cellular and molecular regulation of neurotransmitter release. Recent focus is on the role of neurotrophins in the regulation of normal function and in the remodeling of the enteric nervous system in inflammatory bowel disease.

Dr. DIOMEDES E. LOGOTHETIS

Dr. Diomedes E. Logothetis and his group aim to understand ion channel regulation of gating in molecular terms. They are particularly interested in the regulation of ion channel activity by the βγ subunits of GTP-binding (G) proteins and by signaling phosphoinositides in the inner leaflet of the plasma membrane. Studies utilizing electrophysiology and molecular dynamic simulations are probing channel-PIP2 interactions. Post-translational modifications or protein-protein interactions regulate channel activity in a phosphoinositide-dependent manner and do so by targeting sites proximal to the channel-PIP2 amino acid residues. Ongoing studies are aiming to test the hypothesis that modulators of channel activity that depend on phosphoinositides work by adjusting channel-PIP2 interactions. The physiological implications of regulation of channel activity by G proteins and phosphoinositides is studied in model cells and also examined in cardiac and neuronal systems. Disease models of aberrant phoshoinositide regulation in transgenic animals and neuronal cell lines are being explored.

Dr. Meng Cui works within Dr. Logothetis' lab and their collaborative research focuses on understanding the relationship between structure and function of membrane proteins, such as GPCRs and Ion channels. In this collaborative effort Dr. Cui utilizes computational modeling techniques, molecular mutagenesis and functional expression of the receptors and channels to understand the signal-recognition and transduction mechanism of these important macromolecules. By means of homology modeling, molecular docking, and molecular dynamics approaches, he seeks to understand how ligands or proteins interact and activate their receptors. Extensive long time molecular dynamics simulations based on coarse-grained models are being used to understand the ligand induced activation mechanism of ion channels. He is also developing computational approaches for loop modeling, flexible protein-ligand and protein-protein docking to achieve these goals.

Dr. VIJAY LYALL

Drs. Vijay Lyall and John A. DeSimone are currently studying the cellular basis of the salty and sour modalities of taste. The salty sensation is evoked principally by sodium salts while acids (especially those found abundantly in foods) are potent sour taste stimuli. Studies currently underway include characterization of cellular processes mediating sodium and acid taste reception and inolve a synthesis of systems, cellular, and molecular approaches. A molecular approach to the study of chemoreception is directed by Dr. Anna Vinnikova with the assistance of Dr. Shirley K. DeSimone. They use pharmacological probes that complement the systems and cellular studies and help to provide a better understanding of the cellular mechanisms involved in sensory transduction and adaptation. Molecular biological and immunocytochemical approaches are utilized to confirm the presence and involvement of these molecules in transduction and adaptation.

Dr. LIYA QIAO

The group led by Dr. Liya Qiao focuses on understanding the mechanisms by which the sensory information from the GI tract and urinary bladder is processed at the levels of the enteric nervous system, the dorsal root ganglion (DRG), and the spinal cord. The complex interaction at these levels of sensory processing are examined by applying anatomical, histological, and molecular techniques to isolated neurons, and cultures of spinal cord slices and DRGs from each spinal level. Physiological measurements of gut and bladder function are made in in vivoanimal models and correlated with cellular and molecular data. Recent focus has been on identifying the role of neurotrophins in mediating the viscero-visceral cross-hypersensitivity between bladder and colonic afferent nerve fibers following colonic inflammation.

Dr. I. SCOTT RAMSEY

Dr. I. Scott Ramsey studies proton-selective Hv1 and cation-nonselective TRP ion channels. Hv1 was identified by searching the mammalian genome for novel genes with homology to known voltage-gated channels. Hv1 contains an authentic voltage sensor domain but lacks a pore domain. Surprisingly, expression of Hv1 protein is sufficient to confer a proton conductance that essentially reconstitutes the hallmark biophysical properties of native voltage-gated H+ channels. Dr. Ramsey and his laboratory will use biophysical techniques to elucidate what may be a novel mechanism of ion transport. The cellular and physiological functions of Hv1 are being explored through the use of knockout mice. For example, proton channels may be important for innate immune responses to invading bacterial pathogens. After neutrophils engulf bacteria, they are believed to require a steady supply of protons to make the oxygen free radicals that help to kill the bugs and clear the infection. The laboratory will also investigate the roles of Hv1 in cells and tissues that are not primarily responsible for bacterial clearance. In parallel, the laboratory studies TRP channels, which are sensitive to myriad stimuli such as chemical ligands (e.g. calcium, menthol, capsaicin), thermal energy, electrical field strength, and interactions with both membrane lipids and channel-associated proteins. The lab is investigating gating, channel interactors and expression in a cell-specific context to decipher the molecular control and physiological consequences of TRP channel activity.

Dr. LEI ZHOU

Dr. Lei Zhou and his group focus on the trilogy of structure-dynamics-function for ion channel proteins, specifically, the nature of correlated molecular motions as well as the corresponding changes in response to various external perturbations, such as membrane potential changes and ligand binding. This process begins when an external stimulus triggers changes in the funnel-like protein energy surface, accordingly, the distribution of protein conformation ensemble shifts from the resting state to the activated state. Current research evolves around the protein allostery of ion channels regulated by direct binding of a cyclic-nucleotide (cAMP or cGMP). A multidisciplinary approach including electrophysiology, biochemistry, and computational biology is being applied to test the hypothesis that ion channel’s function closely correlates with not only protein structure but more importantly with protein dynamics. Theoretical approaches being used include normal mode analysis (NMA) and principal component analysis (PCA). Furthermore, coarse-grained computational approaches are being developed to study the effect of surface structural water on protein dynamics. the group studies cyclic-nucleotide activated channels and, in particular, hyperpolarization-activated cyclic nucleotide (HCN) channels found in pacemaker cells in the heart and brain.

VCU Department of Physiology and BiophysicsVirginia Commonwealth UniversityVCU Medical Center
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