Research Areas

Research in gene expression, biochemistry, cell function, and immunology can explain drug action and how derangements in cellular processes lead to disease. Specific research work includes:

• gene expression
• site-directed mutagenesis
• protein purification
• oncogenesis
• signal transduction
• second messengers
• structural and functional characteristics of GTP-binding regulatory proteins, oncogenes, and ion channels by molecular and biochemical techniques
• monoclonal antibodies to define and isolate components involved in mediating cell responsiveness and signaling
• mass spectrometry of DNA adduct formation

Research into the pharmacology of thrombosis and vascular biology, particularly relevant to atherogenesis and the regulation of vascular tone includes:

• lipidomic, genomic and proteomic interrogation of vascular response
• eicosanoid receptor pharmacology in haemopoietic, vascular and cardiac cellscircadian vascular cells
• the use of tissue selective knockout and transgenic technology
• gene therapeutic approaches to vascular biology
• signaling in vascular cells
• isoprostane biochemistry
• regulation of cell cycle kinetics
• integrin receptor pharmacology
• pharmacogenetics – genetic basis of variation in drug response
• effects of lipoproteins and apolipoproteins on the vessel wall
• the pharmacology of hypolipidemic, antihypertensive, anti-inflammatory and anti-thrombotic drugs

This program focuses on the mechanistic links that exist between environmental exposures, the molecular and cellular affects that ensue, and diseases of environmental etiology. Many common diseases/disorders are "linked" to environmental exposures. Areas of interest include: lung and airway disease (asthma, lung cancer, mesothelioma and chronic obstructive pulmonary disease) that can result from exposure to allergens, ozone, inhaled carcinogens, asbestos and air pollutants; diseases linked to oxidative stress (neurodegenerative disease, cardiovascular disease and inflammation), and endocrine, reproductive and developmental disorders (oocyte quality, pre-term rupture of the fetal membranes, hypospadia and cryptochordism). Elucidating the mechanistic links will lead to improved prevention and intervention strategies of major disease. EHS encompasses the study of gene-environmental interactions that influence individual susceptibility to environmental exposures and disease, and exposure biology, which encompasses the development of validated biomarkers for risk assessment. Trainees will receive broad training in these areas for careers in EHS and will be encouraged to be board certified as "Diplomats of the American Board of Toxicology". Research work includes:

• Protein modification in neurodegenerative disease
• Oxidant stress and cardiovascular disease
• Lung cancer and exposure to polycyclic aromatic hydrocarbons
• Endocrine and reproduction disruption and use of transgenics
• Mutagenesis of tumor suppressor genes by reactive oxygen
• Abberant signal transduction and epigenetic effects
• Phase I and II enzymes and toxicant exposure: function and gene regulation
• Molecular epidemiology of environmental disease
• Mass spectral methods to validate biomarkers
• Toxicogenomics (genomic profiling following toxicant insult)
• Toxicoproteomics (proteome changes following toxicant insult)
• Use of toxicants to probe disease mechanism

Using cellular and molecular biological approaches, investigators in neuropharmacology study the interactions of neurotransmitters with receptors and the biochemical and functional effects of these interactions. As such it is a broad field encompassing pharmacological effects upon isolated neurons and glia, on systems neuroscience and on behavior. The work in the Department is fundamental in nature with each PI casting an eye towards the applications of their work to the translational research arena. Ongoing biochemical, morphological, and behavioral studies, which increase understanding of the molecular basis of neuronal function, include:

• use of cell culture techniques to study neuronal and glial signaling pathways as well as neuronal cell death
• probing the relationship between molecular structure and the function of receptors, channels, and transporters
• using cellular and molecular techniques to study trafficking of RNAs and proteins within individual cells
• using biochemical and radiological binding techniques to study functional regulation of receptors
• studying changes in gene expression in response to pharmacological treatment and in transgenic mouse model systems
• studying changes in gene expression in response to pharmacological treatment and in transgenic mouse model systems
• defining changes in neurotransmitter release underlying the effects of psychotropic drugs and drugs of abuse
• studying behavioral responses mediated by specific subtypes of neurotransmitter receptors for catecholamines, serotonin, amino acids, and peptides
• developing high throughput methodologies to screen for compounds that effect neuronal and glial function.

This program focuses on the genetic basis of inter-individual variation in response to various classes of drugs and therapeutic protocols. It encompasses the study of genetic factors (and gene-environment interactions) that influence drug delivery, bio-availability, metabolism and clearance, as well as toxicity. Research work includes:

• The relationship between genotype and disease phenotype and response to therapy.
• Population based disease association studies of polymorphisms of candidate genes.
• Family studies of the inheritance of predisposing genetic factors incorporating transmission disequilibrium tests and assessments of maternal genotypic effects on fetal pathology.
• Epidemiology of common disorders.
• Bio-informatics and the maximization of the efficiency and information content of data analysis.
• The importance of genetic factors in planning and evaluating dose finding studies.
• Theoretical considerations of the impact of genetically determined differential drug responses in the planning, execution and interpretation of clinical trials.
• Development of transgenic models to analyze drug-genotype interactions in different environmental situations and in the context of other disease causing genetic factors.
• Development of expression profiling methods that can be used to track the natural progression of a tissue pathology and to monitor tissue responses to drug therapy.
• Ethical issues concerning informed consent and the exploitation of genetic information in drug discovery and drug evaluation.

This program stresses the chemistry of molecular recognition to understand better drug and carcinogen interactions with receptors (membrane–bound and nuclear receptors, enzymes, or nucleic acids). Techniques include site-directed mutagenesis, affinity-labeling, crystallography, computer-modeling, and synthetic and analytical chemistry. Research work includes:

• affinity-labeling and computer-modeling techniques to define the three-dimensional shape of the ligand binding site of a drug receptor or target enzyme
• identifying the pharmacophore (atomic arrangement essential for pharmacological activity) of various drugs
• studying the three-dimensional structure of the receptor and its ligand to improve therapeutic agents
• bioengineering ion-channels, chimeric receptors and enzymes with altered specificity/function
• synthesizing receptor subtype specific ligands and isoform enzyme inhibitors
• mass spectrometric analysis of carcinogen-DNA adducts
• X-ray crystallography of membrane bound drug targets