My research focuses on developing biologically based models for the uptake, distribution, metabolism, and biological effects of drugs and chemicals and their application to safety assessments and quantitative health risk assessments. In recent years, my research emphasis has been on developing mathematical descriptions of control of genetic circuitry and the dose-response and risk-assessment implications of these control processes.
We study arterioles that vascular resistance in healthy kidneys and kidneys of genetic hypertensive animals or those with mutated selected genes. Measurements include renal vascular reactivity in vivo and receptor/calcium signaling in vitro.
My lab uses a cognitive neuroscience approach to understand the neurobiology of drug addiction in humans. The tools we use include fMRI, cognitive testing, physiological monitoring, pharmacology, and genetic testing. We specifically seek to determine 1) how the brain learns new stimulus-response associations and replaces learned associations, 2) the neurobiological mechanisms underlying the tendency to select immediate over delayed rewards, and 3) the neural bases of addiction-related attentional bias.
This multidisciplinary laboratory has 6 interests: 1) Defining regionally specific adaptations responsible for functions altered by chronic ethanol; 2) Characterizing regional CNS biochemical changes induced by stress and CRF after chronic ethanol; 3) Defining the role of central cytokines in behaviors induced by stress; 4) Exploring how a benzodiazepine (BZD) agonist shares actions with a BZD antagonist; 5) Defining TRH receptor subtype(s) responsible for its anti-anxiety and analeptic actions; and 6) Defining the action of galanin on ethanol withdrawal-induced anxiety. To undertake our interests, behavioral, anatomical, pharmacological, electrophysiological, biochemical, and molecular biological approaches are used.
Research in the Brouwer laboratory is focused on: (1) hepatobiliary xenobiotic disposition, including mechanisms of hepatic uptake, translocation and biliary excretion; (2) development/refinement of in vitro model systems to predict in vivo hepatobiliary disposition, drug interactions, and hepatotoxicity; (3) hepatic drug transport; and (4) pharmacokinetics, including aberrant gastrointestinal drug absorption phenomena.
Research in the Carelli laboratory is in the area of behavioral neuroscience. Our studies focus on the neurobiological basis of motivated behaviors, including drug addiction. Electrophysiology and electrochemistry procedures are used during behavior to examine the role of the brain 'reward' circuit in natural (e.g., food) versus drug (e.g., cocaine) reward. Studies incorporate classical and operant conditioning procedures to study the role of the nucleus accumbens (and dopamine) and associated brain regions in learning and memory, as they relate to motivated behaviors.
We study cell cycle control of DNA replication licensing, the process that renders replication origins competent to initiate DNA synthesis. We investigate how the replication process is linked to cell cycle progression and the signaling pathways that gather and transmit information about the cellular environment. Our experimental approach is to manipulate human cells in culture (both cancer cell lines and normal cells) through a variety of molecular and genetic strategies; some projects utilize budding yeast as a model system due to the sophisticated genetic tools available in that organism. We measure protein abundance and stability, chromatin localization and modifications, cell cycle progression, protein-protein interactions, and checkpoint functions. Our long-term goals are to understand the molecular events that ensure genome stability and how those events are disrupted in cancer cells.
The direct fabrication and harvesting of monodisperse, shape-specific nano-biomaterials are presently being designed to reach new understandings and therapies in cancer prevention, diagnosis and treatment.
My interests focus on developing quantiative methods to assess the relationships between exposure, dose and response. This research has examined methods for dioxins, thyroid hormone disruptors and pyrethroid pesticides.
We use an integrated approach (genomics, proteomics, computational biology) to study the molecular mechanisms of hormone and drug desensitization. Our current focus is on RGS proteins (regulators of G protein signaling) and post-translational modifications including ubiquitination and phosphorylation.
The study of opioid analgesics, with particular focus on opioids that are less likely to produce physical dependence and abuse. Research in the laboratory has examined the relationship between the analgesic effects of opioid analgesics and their interaction with specific opioid receptor types. A more recent research interest includes investigations of genetically-altered mice with relevance to drug dependence and the development of models of mouse behavior for examining behavioral phenotypes related to a range of behavioral disorders.
Our lab is interested in how signals from membrane receptors are transduced to the nucleus altering gene expression, cell shape, proliferation and differentiation. We are particularly interested in tyrosine-specific protein kinases in breast and prostate cancer, as well as lymphoma/leukemia. Particular focus of the lab include:1) roles of the EGF receptor family and related molecules HER4/ErbB4 in growth inhibition and differentiation and 2) Mer (a novel receptor tyrosine kinase) and how signals downstream from Mer enhance prostate tumorigenesis.
The Elston lab is interested in understanding the dynamics of complex biological systems, and developing reliable mathematical models that capture the essential components of these systems. The projects in the lab encompass a wide variety of biological phenomena including signaling through MAPK pathways, noise in gene regulatory networks, airway surface volume regulation, and understanding energy transduction in motor proteins. A major focus of our research is understanding the role of molecular level noise in cellular and molecular processes. We have developed the software tool BioNetS to accurately and efficiently simulate stochastic models of biochemical networks
The role of associative learning and memory in cue-induced relapse to drug seeking and the role of the prefrontal cortex in suppression of drug seeking. Studies in my laboratory utilize surgical, behavioral, and histological techniques as well as neuropharmacological manipulations.
Our lab is studying the role of mitogen and stress-activated protein kinases to regulate key aspects of cell metabolism. We are also studying signalling by tyrosine kinases in response to toxicological agents or cell stress.
The primary thrust of research in this lab seeks to understand the effects of neurosteroids on development, particularly how neurosteroid levels in the developing cortex affect patterns of migration and neurogenesis in the prefrontal cortex. A secondary interest is the mechanisms by which increases in neurosteroid levels might be relevant to their therapeutic action.
We focus on mechanistic/structural aspects of regulatory proteins (heterotrimeric and Ras family GTPases, RGS proteins, and PLC isozymes) involved in inositol lipid signaling, and on G protein-coupled receptors for extracellular nucleotides.
The Neurotoxicology Group examines the role of microglia interactions with neurons and the associated immune-mediated responses in brain development and aging as they relate to the initiation of brain damage, the progression of cell death, and subsequent repair/regenerative capabilities. We have an interest in the neuroimmune response with regards to neurodegenerative diseases such as, Alzheimer's disease.
Effects of drugs of abuse on maternal behavior and aggression and the effects of prenatal exposure to drugs on offspring development and behavior. Approaches range from molecular to behavioral as our work is basic science with a clinically applicable focus.
Signal transduction coupled by heterotrimeric G proteins. We use Arabidopsis, genetics, biochemistry, & in vivo imaging of protein-protein interactions. The type of signals we study include light, hormones, & sugars.
Research interests include: 1) Regulation of signal transduction and cell growth by integrin-mediated cell adhesion and 2) Therapeutic drug design and delivery.
Dr. Maixner’s research program focuses on identifying the pathophysiological processes that underlie pain perception, persistent pain conditions, and related disorders. His current research focuses on genetic, environmental, biological, and psychological risk factors that contribute to the onset and maintenance of chronic pain conditions. A long term goal of his program is to translate new discoveries into clinical practices that improve the ability to diagnose and treat patients experiencing chronic pain.
Physiology and pharmacology of the basal ganglia; neurobiology of motivation and reward; substance abuse neurobiology; and neurobehavioral teratology.
My laboratory studies the function of neural circuitry involved in the perception of reward and the reinforcement of motivated behaviors in several mouse models of neurodevelopmental disorders, including early developmental exposure to drugs of abuse, such as alcohol or cocaine; and genetic models relevant to the study of autism, such as inactivation of the Fmr1 (Fragile-X Mental Retardation) or MeCP2 (Methyl-CpG Binding Protein) genes. My laboratory employs techniques in behavioral pharmacology, including intracranial self-stimulation (ICSS); in vitro patch-clamp electrophysiology in acute brain slices; and immunohistochemistry with unbiased stereological microscopy.
Dr. Meeker’s research is focused on the mechanisms of HIV neuropathogenesis. Inflammatory changes within the brain caused by the viral infection initiate a toxic cascade that disrupts normal neural function and can eventually lead to neuronal death. To explore the mechanisms responsible for this damage, we investigate changes in calcium homeostasis, glutamate receptor function and inflammatory responses in primary neuronal, microglial and macrophage cultures. New therapeutic approaches targeted to signal transduction pathways and calcium regulation that protect the neurons and reduce inflammation are under investigation.
The goal of the laboratory’s research is to define the structure and function of an intracellular Ca2+ release channel in skeletal and cardiac muscle, using molecular biological and electrophysiological methods and by creating mutant mice.
My laboratory studies diffuse gliomas, devastating primary tumors of the central nervous system for which few effective drugs are currently available. We utilize model systems (genetically engineered mice, cultured cells, and human tumor specimens) to explore the molecular pathogenesis of
and develop drugs and diagnostic markers for individualized therapy of gliomas. Rotating students gain experience with techniques that include genomics (expression microarrays and array CGH), fluorescence microscopy, computer-enhanced image analysis, and tissue microarrays.
Function, expression and trafficking GABA-A receptors in the CNS; effects of chronic ethanol exposure that leads to ethanol tolerance and dependence; role of endogenous neurosteroids on ethanol action and adaptations; etiology of essential tremor.
My research interests include the endocrinology of pregnancy and parturition; reproductive and developmental toxicity testing; mixtures toxicology; structure-activity relationships; axial skeletal development; and strain differences in toxic responses.
My laboratory has two main interests: 1) P2Y receptor trafficking in epithelial cells. Our laboratory investigates the cellular and molecular mechanisms by which P2Y receptors are differentially targeted to distinct membrane surfaces of
polarized epithelial cells and the role of lipid rafts and caveolae in P2Y receptor function. 2) Antibiotic resistance mechanisms. We are interested in the mechanisms of antibiotic resistance in the pathogenic bacterium, Neisseria gonorrhoeae. Our laboratory investigates how acquisition of mutant alleles of existing genes confers resistance to penicillin and cephalosporin. We also study the biosynthesis of the gonococcal Type IV pilus and its contribution to antibiotic resistance.
Using a combination of in vivo and in vitro approaches, our lab studies the extracellular cues and intracellular signaling pathways regulating neuronal migration, axon guidance and dendritic differentiation during early aspects of brain development.
The nucleus accumbens is a limbic-motor integrator, assimilating memory and drive input and coordinating responsive behavioral output. Anatomical and pharmacological evidence indicates that the core and shell subregions of the nucleus accumbens perform overlapping but distinct roles in motivated behavior. My experiments examine nucleus accumbens core and shell function during ethanol drinking behavior in rats, with particular focus on how dopamine input modulates accumbal activity on the millisecond timescale. I use two approaches: electrophysiological firing patterns of neurons in the nucleus accumbens core and shell are evaluated using multi-electrode arrays, and phasic (subsecond) dopamine activity is evaluated using fast-scan cyclic voltammetry. I am also interested in exploring the pharmacological manipulation of neuronal transmission in the nucleus accumbens, focusing on drugs that have clinical therapeutic value in treating alcoholism.
Ion channels and ionotropic receptors. Molecular mechanisms of ligand binding, channel activation, ion selectivity, and allosteric modulation. Techniques used: Molecular modeling, site directed mutagenesis, heterologous expression in Xenopus oocytes and other cells, chemical modification, and voltage clamp electrophysiology.
Bioinformatics, Cancer Biology, Cell Biology, Chemical Biology, Computational Biology, Genomics, Molecular Medicine, Neurobiology, Pharmacology, Systems Biology, Toxicology, Translational Medicine
Regulator of G-protein signaling (RGS) proteins accelerate the GTPase activity of G-alpha subunits and thereby act as critical negative regulators of hormone and neurotransmitter signaling via G protein-coupled receptors. Our lab first recognized the existence of these critical signaling regulators in 1996. We continue to study their structural and functional diversity, as well as their roles in physiological and disease processes, including immunity, oncogenic transformation, and pain processing.
Dr. Smith’s research interests are in correlating pharmacokinetics and metabolism of drugs with their pharmacodynamics and toxicity. Research efforts in this area include in vitro studies and in vivo animal experiments aimed at understanding mechanisms of processes that influence drug disposition and toxicity. Where possible, transitional studies in human subjects are conducted to demonstrate clinical relevance and the potential application to humans. A primary emphasis in the laboratory is the process of glucuronidation, the major Phase II metabolic pathway where the sugar, glucuronic acid, is coupled to drugs and other xenobiotics.
I study complex traits using linkage, association, and genetic epidemiological approaches. Disorders include schizophrenia (etiology and pharmacogenetics), smoking behavior, and chronic fatigue.
My primary research interests are directed at the neurobiology of alcoholism. To study the central mechanisms involved with neurobiological responses to ethanol, I use both genetic and pharmacological manipulations. There are many factors that may cause an individual to progress from a moderate or social drinker to an alcoholic. In addition to environmental influences, there is growing evidence in both the human and animal literature that genetic factors contribute to alcohol abuse. Furthermore, the risk for developing alcoholism is likely not associated with a single gene, but rather with multiple genes that interact with environmental factors to determine susceptibility for uncontrolled drinking. Some of the questions that my laboratory is currently addressing are: 1) Does central neuropeptide Y (NPY) signaling modulate neurobiological responses to ethanol and ethanol consumption, 2) Do melanocortin peptides modulate ethanol intake? and 3) Does cAMP-dependent kinase (PKA) play a role in voluntary ethanol consumption and/or other effects produced by ethanol?
Dr. Tidwell's research is focused on the design and synthesis of new drugs for the treatment of AIDS-associated opportunistic infections. The rationale for design of new drugs is directed at determining the mechanisms of action, antimicrobial activity, and pharmacokinetics of dicationic molecules. Studies have been initiated to isolate and identify new drug targets from Pneumocystis carinii and Cryptosporidium parvum utilizing molecular modeling and biochemical methods to aid in the determination of new structures. The role of proteases and imidazoline receptors in the pathogenesis of disease continues to be a major area of research as well as a new prodrug approach for the cationic molecules to allow for much improved bioavailability.
Our work focuses on molecular aspects of androgen receptor regulation of gene expression, which includes coactivator interactions with the androgen receptor and its functional importance in various clinical syndromes.
