Synapses are the primary points of communication between cells of the nervous system. Our laboratory is interested in synaptic receptors and ion channels. We study the molecular events that constitute agonist binding, channel activation and receptor desensitization. Our research bridges physiology pharmacology, biochemistry and structural biology, and our experimental approaches include electrophysiology, computational chemistry (MD simulations) and molecular biology. We seek to to understand the molecular operation of receptors and other allosteric membrane proteins in the context of their physiological roles. CONTACT INFORMATION: email@example.com (716) 510-0793
We study the regulation of ion transport in epithelia. We are interested in a sodium channel expressed in many epithelia throughout the body. In the kidneys, this channel and its regulation, modify renal sodium excretion and body sodium balance. We are interested in mechanisms which control channel activity and more specifically, in the mechanism of channel activation from the extracellular space. Our lab is also interested in the translational aspect of channel activation and specifically in the discovery of biomarkers of channel activators. These biomarkers can likely report on channel activation in vivo and in this case, can serve can predictors of human hypertension
The focus of my research is on understanding the comparative neurochemical organization of brainstem and cerebellar structures that mediate balance, posture and movement and analyzing how this organization may vary with development, learning, aging, gender or neurological disease. I am also interested in how these systems have changed over evolution, and am comparing brainstem and cerebellar organization in humans and apes.
Gastroenterology; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular and Cellular Biology
Research in my laboratory concerns neurotransmitter and hormone-mediated anion secretion by gastrointestinal secretory tissues like intestinal crypts and liver ducts. I am determining the mechanisms that regulate the basolateral membrane K+ channel, KCNQ1, in anion secretion because these channels play a critical role in secretion by maintaining membrane potential as a driving force for anion exit across the apical cell membrane. Characterization of KCNQ1 K+ channels will help us to understand and remedy defects in anion secretion, especially in diseases like cystic fibrosis. I use electrophysiological techniques, including Ussing chamber, patch-clamp, and Fura-2 fluorescence techniques. I am also studying the mechanisms by which K+ channel antagonists (e.g., Zn2+) block KCNQ1 channels so that anti-secretory, anti-diarrheal drugs can be developed. I have past experience determining the mechanisms by which neurotransmitters regulate K+ channels via inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release transduction pathways. I am also collaborating with Dr. John Crane to define the mechanisms by which Zn2+ inhibits the effects of Enteropathogenic E. coli (EPEC) on epithelial cell death and EPEC-stimulated phosphorylation and activation of the CFTR Cl- channel. There is considerable controversy concerning the role and basis of GI disorders associated with autism. In collaboration with Drs. Randall Rasmusson and Glenna Bett, I am investigating the mechanistic link between autism susceptibility and abnormal GI function. I propose that disorders of cellular Ca2+ homeostasis play a key role in the GI disorders of autism. Using mouse models derived from Cav1.2 Ca2+ channel defect that produces the human disorder, Timothy Syndrome, I am characterizing muscle tension and electrophysiological properties of the Ca2+ channel in intestinal smooth muscle. This information will lead to new approaches to identify therapeutic targets and treatments for autistic spectrum GI disorders and symptoms.
Neurology; Neurodegenerative disorders; Pathophysiology; Apoptosis and cell death; Cytoskeleton and cell motility; Molecular and Cellular Biology; Molecular genetics; Neurobiology; Protein Folding; Gene Expression; Transcription and Translation; Signal Transduction; Toxicology and Xenobiotics
My research is aimed at finding the cause and a cure for Parkinson’s disease. Parkinson’s disease (PD) is defined by a characteristic set of locomotor symptoms (rest tremor, rigidity, bradykinesia and postural instability) that are believed to be caused by the selective loss of dopaminergic (DA) neurons in substantia nigra. The persistent difficulties in using animals to model this human disease suggest that human nigral dopaminergic neurons have certain vulnerabilities that are unique to our species. One of our unique features is the large size of the human brain (1350 grams on average) relative to the body. A single nigral dopaminergic neuron in a rat brain (2 grams) has a massive axon arbor with a total length of 45 centimeters. Assuming that all mammalian species share a similar brain wiring plan, we can estimate (using the cube root of brain weight) that a single human nigral dopaminergic neuron may have an axon with gigantic arborization that totals 4 meters. Another unique feature of our species is our strictly bipedal movement, which is affected by Parkinson’s disease, in contrast to the quadrupedal movement of almost all other mammalian species. The much more unstable bipedal movement may require more dopamine, which supports the neural computation necessary for movement. The landmark discovery of human induced pluripotent stem cells (iPSC) made it possible to generate patient-specific human midbrain dopaminergic neurons to study Parkinson’s disease. A key problem for dopaminergic neurons is the duality of dopamine as a signal required for neural computation and a toxin as its oxidation produces free radicals. Our study using iPSC-derived midbrain dopaminergic neurons from PD patients with parkin mutations and normal subjects shows that parkin sustains this necessary duality by maintaining the precision of the signal while suppressing the toxicity. Mutations of parkin cause increased spontaneous release of dopamine and reduced dopamine uptake, thereby disrupting the precision of dopaminergic transmission. On the other hand, transcription of monoamine oxidase is greatly increased when parkin is mutated. This markedly increases dopamine oxidation and oxidative stress. These phenomena have not been seen in parkin knockout mice, suggesting the usefulness of parkin-deficient iPSC-derived midbrain DA neurons as a cellular model for Parkinson’s disease. Currently, we are using iPS cells and induced DA neurons to expand our studies on parkin to idiopathic Parkinson’s disease. We are also utilizing the molecular targets identified in our studies to find small-molecule compounds that can mimic the beneficial functions of parkin. The availability of human midbrain DA neurons should significantly speed up the discovery of a cure for Parkinson’s disease.
Pathophysiology; Cytoskeleton and cell motility; Endocrinology; Eukaryotic Pathogenesis; Gene Expression; Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure; Regulation of metabolism; Transcription and Translation
In my laboratory, we are interested in structural components of the cell, their role in establishing and regulating cellular functions, and how this regulation translates into physiological consequences in health and disease. We have two major focus areas: 1) The role of cytoskeletal elements in prostate cancer development and progression and 2) The role of nucleoskeletal elements in establishing and maintaining nuclear structure and function. 1) The majority of death from cancer is caused by metastasis, the spreading of cancer cells from the site of a primary tumor to other body parts. We use a combination of biochemical, cell biological, physiological, and translational approaches to elucidate the mechanisms that are involved in the acquisition of metastatic phenotypes. Specifically, we focus on the role that myosins play in this process. We are also interested in how dietary fats can contribute to the development of metastatic phenotypes in prostate cancer cells. 2) Aberrations in nuclear structure and dynamics are the underlying cause of diseases ranging from cancer to premature aging. We are interested in the role of nuclear actin and myosins in regulating dynamic nuclear processes such as nucleolar assembly and functions in health and disease.
Inherited Metabolic Disorders; Membrane Transport (Ion Transport); Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure; Transgenic organisms; Vision science
Most physiological processes and numerous disease states influence or are influenced by pH. Even relatively small deviations in whole body pH can have devastating consequences for our health. Our bodies are subject to a constant challenge from dietary and metabolic acids, thus it is critical for the body to have mechanisms that tightly regulate pH. Blood plasma pH is maintained at a value close to 7.4, predominantly thanks to the buffering action of 24 mM bicarbonate (HCO3-). HCO3- neutralizes acid, generating carbon dioxide and water (HCO3- + H+ to CO2 + H2O), preventing lethal acidosis. I study the SLC4 family of membrane proteins that move acid/base equivalents across cell membranes. Notable members include  the Na/2HCO3 cotransporter NBCe1-A that reclaims HCO3- from filtered blood plasma in kidney tubules (preventing loss of vital plasma HCO3- to the urine),  NBCe1-B that promotes fluid removal from the corneal stroma (preventing corneal edema and vision loss),  the Cl-HCO3 exchanger AE1 that promotes O2-CO2 exchange in red blood cells, and  SLC4A11 that conducts H+ and promotes corneal clarity. Dysfunction of SLC4 family members is associated with renal tubular acidosis, blindness, cancer, deafness, epilepsy, and hypertension. Course Director for PGY405/505 (Cellular and Molecular Physiology) Course Co-Director for IMC512 (Renal Module)
Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular Basis of Disease; Molecular and Cellular Biology; Protein Folding; Protein Function and Structure; Signal Transduction
Work in my lab seeks to elucidate the transduction mechanisms of ion channels involved in thermal sensation and pain, such as the heat-activated vanilloid receptors (TRPV1-4) and the cold-activated TRPM8 – the so-called thermal TRP channels. Expressed in peripheral afferent nerve endings, these channels function as an array of thermometers for sensing ambient temperature from noxious cold to noxious hot. While all proteins are thermally sensitive, thermal TRP channels are gated by temperature and possess unprecedentedly high temperature dependence. But the mechanisms of their temperature gating has remained mysterious, in contrast to our abundant knowledge on other types of ion channel gating (e.g. voltage or ligand-driven). Thermal TRP channels are also distinct for their polymodal responsiveness. TRPV1, for example, is responsive to heat, voltage, pH, capsaicin (i.e. the hot ingredient of chili peppers) among many other irritant compounds. The channels are thus informative for deciphering how biological proteins achieve multitasking. Thermal TRP channels also have receptor-like roles in mediating intracellular signaling. The calcium influx through the channels has potentially a broad spectrum of functional consequences, one of which is the desensitization of the channels themselves, a phenomenon that is believed to underlie peripheral analgesics. Our research is centered on problems like these, and we approach them by a combination of techniques such as recombinant mutagenesis, patch-clamp recording, fluorescence measurements, quantitative modeling, etc, which together allow us to draw insights into functions of the channels at mechanistic levels. Complementing our experimental studies, we are also interested in development of methodology to ever extend experimental resolutions. For example, to time-resolve temperature-dependent activation of thermal TRP channels, we have developed a laser diode-based temperature clamp apparatus, which achieves for the first time a submillisecond resolution (>105 oC/s) while capable of clamping temperature constant. For the past decade we have also been developing sophisticated algorithms for statistical analysis of single-molecule measurements such as single-channel patch-clamp recordings, which can help unravel the richness of data pertaining to molecular mechanisms at high resolutions. Together, these approaches provide us with unique abilities for in-depth studies of structure-mechanisms of ion channels.
Cardiopulmonary physiology; Cytoskeleton and cell motility; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular and Cellular Biology; Molecular Basis of Disease; Signal Transduction
My research interests center on mechanical and electrical biophysics, from molecules to organs, and the development of new tools. And, in recent years I worked in transitional science; bringing basic science to the clinic and to industry. My basic research interests are on cell mechanics and the mechanisms by which mechanical forces are transduced into messages such as voltage and chemicals such as ATP and Ca2+. I discovered mechanosensitive ion channels in 1983. My methodology has included patch clamp, high resolution bright field light microscopy, low light fluorescence microscopy, high speed digital imaging, TIRF, digital image analysis, high voltage EM with tomography, Atomic Force Microscopy, molecular biology, natural product and recombinant protein biochemistry, NMR and microfabrication and microfluidics. We discovered the only known specific inhibitor of mechanosensitive ion channels and uncovered its remarkable mode action by using a combination of electrophysiology and chiral chemistry. We have demonstrated potential clinical applications of the peptide for cardiac arrhythmias, oncology, muscular dystrophy, and incontinence. We have developed many scientific tools. Recently we developed a sensor chip to measure cell volume in real time, and that is now entering production with Reichert Instruments of Buffalo. We also have an Small Business Innovation Research contract to develop a microfluidic, bipolar, temperature jump chip with ALA Scientific and developed a microfabricated Atomic Force Microscopy probe that is an order of magnitude faster and more stable than any commercial probes. We have made probe operable with two independent degrees of freedom on a standard Atomic Force Microscopy. This permits us to remove all drift and coherent noise by using one axis to measure the substrate position and the other the sample position. These probes are being produced by a new company in Buffalo, kBtwist. We have used the Atomic Force Microscope combined with electrophysiology to study the dynamics of single voltage dependent ion channels. This technique provides a resolution of >0.01nm in a kHz bandwidth. I have developed other hardware including the first automated microelectrode puller, a micron sized thermometer and heater and a high speed pressure servo. Some of these devices have been patented by the University of Buffalo and some are in current production. To analyze the reaction kinetics of single molecules, we developed and made publicly available (www.qub.buffalo.edu) a complete software package for Windows that does data acquisition and Markov likelihood analysis. The development was funded by the National Science Foundation, National Institutes of Health and Keck over the last fifteen years, and has been applied to ion channels, molecular motors and the even the sleep patterns of mice. We have taught at UB hands-on course to use the software, and the course was attended by an international group of academic scientists and students, government and industry.
The laboratory seeks to understand information processing in the retina, a model for neural network analysis. Studies focus on the events that occur at synapses, with a particular emphasis on neurotransmitter-receptor interactions. Not only the neurotransmitter type but also the properties of receptor subtypes determines how neurons communicate. Our experiments investigate this linkage using electrophysiological, molecular and cell-imaging techniques. Subjects of current interest are: 1) synaptic communication by metabotropic receptors 2) properties of glycine receptors in retina and in expression systems; 3) acetylcholine-based signal transmission; 4) image-based analysis of retinal function. There is also a clinical application to the electroretinogram, a tool used by ophthalmologists to evaluate the health of the retina. We are able to use our knowledge of complex retinal circuits to improve the analytical potential of the electroretinogram. Transmitter-receptor interactions also form the basis for many pharmaceutical agents used to treat neurological problems. Therefore our retinal studies apply to the broad area of medicinal pharmacology.
My research is aimed at determining how nerve cells establish appropriate connections during the development and regeneration of axonal connections. In recent years, my work has focused on the role of glutamate receptors in the development and regeneration of connections between the spinal cord and the muscle at the neuromuscular junction. Under normal conditions, each muscle fiber is innervated by a single nerve fiber, and Dr. Kirk Personius and I have demonstrated that glutamate receptors are integral to these processes. Until our work, this transmitter system had never been examined as a contributing factor. We now are exploring the mechanisms by which glutamate influences these important events. For many years prior to this work, I studied related questions in a very different system. My work focused on how early visual input influences the formation of topographic binocular connections in the midbrain optic tectum of the frog, Xenopus laevis. The relay for visual input from each eye to the ipsilateral tectum, is a tegmental structure called the nucleus isthmi. The axons from this structure are guided to the optic tectum by unknown non-visual processes, but within the tectum, their final connections are completely dependent on the visual input coming from the 2 eyes. Only if both eyes are open, optically normal and exposed simultaneously to patterned input, will the isthomotectal projection form a map of the ipsilateral eye‘s field which is in proper topographic registration with the contralateral eye‘s field. Absence of visual input during development prevents the isthmic axons from terminating in a topographically organized way, and strabismus causes the isthmic axons to form an orderly but abnormal map which is in register with the map from the misaligned eye. The NMDA (N-methyl-D-aspartate) glutamate receptor is essential to this process, and the transmitters acetylcholine and GABA also are being investigated for their roles in control of plasticity. The techniques that have been used in these experiments include extracellular electrophysiological recording methods, immunocytochemistry, electron microscopy, calcium imaging, receptor binding, whole-cell patch-clamping, knockdown techniques to control activation of transmitter systems, and anatomical tracing methods.
Cardiology; Cardiovascular Disease; Stem Cells
My research program is focused on the investigation of mechanisms underlying functional and structural cardiac remodeling in heart disease, as well as novel therapeutic interventions to prevent or reverse left ventricular dysfunction caused by myocardial ischemia and hemodynamic overload. These studies generally utilize non-invasive cardiovascular imaging techniques and invasive hemodynamic assessment to assess cardiac performance in vivo, along with ex vivo analysis of myocardial tissue to examine cellular and molecular mechanisms underlying observed changes in physiological function.
Neurodegenerative disorders; Pathophysiology; Cytoskeleton and cell motility; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Neuropharmacology; Signal Transduction
Synaptic Mechanisms of Mental Health and Disorders Our research goal is to understand the synaptic action of various neuromodulators that are linked to mental health and illness, including dopamine, stress hormones, and disease susceptibility genes. Specifically, we try to understand how these neuromodulators regulate glutamatergic and GABAergic transmission in prefrontal cortex (PFC), which is important for emotional and cognitive control under normal conditions. We also try to understand how the aberrant action of neuromodulators under pathological conditions leads to dysregulation of synaptic transmission in PFC, which is commonly implicated in brain disorders. The major techniques used in our studies include: • whole-cell patch-clamp recordings of synaptic currents, • viral-based in vivo gene transfer, • biochemical and immunocytochemical detection of synaptic proteins, • molecular analysis of genetic and epigenetic alterations, • chemogenetic manipulation of neuronal circuits, • behavioral assays. By integrating the multidisciplinary approaches, we have been investigating the unique and convergent actions of neuromodulators on postsynaptic glutamate and GABAA receptors, and their contributions to the pathogenesis of a variety of mental disorders, including ADHD, autism, schizophrenia, depression, PTSD and Alzheimer‘s disease.