Department of Pharmacology

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Thematic Programs

Cancer Pharmacology

Research and training in Cancer Pharmacology is at the interface of characterizing fundamental processes in cancer biology and understanding the mechanisms of actions of agents that modulate proliferation, survival, mutagenesis, and tumorgenesis. Diverse research approaches are being used and range from modern techniques in cell and molecular biology using in vitro model systems to in vivo models of carcinogenesis to cutting edge analytical approaches to identify and measure DNA adducts and mutations. Major areas of research include defining and characterizing disordered signaling pathways in cancerous cells, mass spectrometry analysis of DNA modifications and vital cellular structures by carcinogens, and actions of anticancer drugs at both the basic and clinical levels. Research and training in basic and clinically related cancer pharmacology are enhanced by the multi-disciplinary and integrated approach provided by the Center for Cancer Pharmacology which serves as a focal point for research and training in cancer pharmacology. Course work emphasizes broad training in the fundamentals of cell biology, pharmacology, mechanisms of carcinogenesis, eukaryotic molecular genetics, and signal transduction, along with courses specifically focused on cancer pharmacology and new pharmacology-based methods for treating cancer. For more information on research and training see: http://www.med.upenn.edu/ccp/.

Cardiovascular Pharmacology

Research and training in Cardiovascular Pharmacology focuses on vascular biology and thrombosis. Research programs explore the cellular and molecular basis of atherogenesis and thrombosis using a variety of approaches including knockout and transgenic technologies, gene therapy techniques, and modern approaches in chemistry, biochemistry, molecular biology and cell biology. Through multi-disciplinary research projects, collaborative research grants, and seminar series the Cardiovascular Pharmacology program is closely integrated with research groups in the Department of Medicine, the Institute of Medicine and Engineering, and the Wistar Institute. Research in the pharmacology of thrombosis and vascular biology focuses on understanding the roles of proteins, lipids, and small molecule mediators of cardiovascular function and dysfunction. Particular efforts are directed at understanding the pharmacology and signaling of eicosanoids, thrombin, integrins and adenosine in vascular and cardiac cells as well as isoprostane biochemistry and the pharmacology of lipid mediators of cardiovascular function. Understanding mechanisms of pathophysiology and actions of drugs under normal and pathophysiological conditions is the focus of research investigating the response of vessel walls to apoplipoproteins and defining molecular actions of hypolipidemic, antihypertensive, antiinflammatory and antithrombotic drugs. Didactic and literature survey courses in Cardiovascular Pharmacology along with research rotations covering a broad range of techniques and approaches provide students with a strong foundation to pursue thesis research in the area of Cardiovascular Pharmacology.

Cell Signaling

The mechanisms by which signals converging on cells are perceived and translated into appropriate cellular responses represent a fundamental aspect of pharmacological inquiry. Signals of special interest include hormones, neurotransmitters, sensory stimuli, and cell-cell or cell-substratum contacts. Understanding the range and nature of cellular signals is an important pursuit, as over 80% of all therapeutic agents currently in use operate through mimicry or antagonism of such signals, a value not likely to decrease as receptors for these signals continue to emerge at a high pace through genomic screens. Understanding derangements in signaling is an equally important pursuit, as a vast number of human disorders, ranging from cancer to neuropsychiatric deficits, are related to abnormal signaling.

Some components of the curriculum cover signaling alone, permitting an exacting and quantitative treatment of the subject. Others place signaling in the context of additional pharmacological and pathophysiological disciplines. The integrative aspects of research in signaling are reinforced by journal clubs, seminars, and actively shared interests among laboratories.

Approximately 40 laboratories within the Pharmacology Graduate Group carry out basic research in cell signaling. Research topics include structural and functional characteristics of cellular receptors, G-proteins and adaptor molecules, and signal transduction pathways including post-translational protein modification and ion homeostasis in diverse models of pathological and physiological processes and specific disease conditions. The methodological approaches employed rely on the most sophisticated cell and molecular biological technologies available.

Examples of specific research work include:

Impact of signaling on gene expression, cell morphology, cell proliferation, apoptosis, and, upon integration, cell function at an organism

Environmental Health Sciences (EHS)

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:

Neuropharmacology

In terms of morbidity, mortality, and dollars spent, the cost of neurologic and psychiatric disorders to society is phenomenal. Stroke and traumatic brain injury represent the number one cause of disability and the third leading cause of death in the United States. Ten percent of the population experiences at least one major depressive episode during life. Over 4 million people have Alzheimer’s Disease today and this is projected to increase dramatically in the future.

The overall focus of Neuropharmacology research and training is to provide students with an integrated understanding of the interactions of neurotransmitters with receptors and the biochemical and functional effects of these interactions. Over twenty laboratories use a variety of modern cellular, molecular, genetic, and behavioral strategies to study the molecular bases of brain function. Some laboratories use genetically engineered mouse models to study diverse issues, including the role of individual neurotransmitters/ signaling molecules in complex behaviors such as drug addiction, memory formation, Alzheimer’s Disease, and depression. Other laboratories use cellular systems to study issues ranging from receptor function and trafficking of RNAs and cellular proteins to cell death. The program includes a series of specialized courses that introduce students to the broad area of Neuropharmacology and is supported in part by a longstanding NIH funded training grant. Several different program projects/center grants support Faculty in the Program providing many opportunities for the development of collaborative research projects that enhance the quality of the training. Areas of expertise of these centers include: Traumatic Brain Injury, Serotonin Receptors in the Brain, Alzheimer’s Disease, and Mental Retardation and Developmental Disabilities Research.

Pharmacogenetics

Pharmacogenetics focuses on the genetic basis of inter-individual variation in response to various classes of drugs and therapeutic protocols and makes use of this information to develop rationale therapeutic regimens and to identify genetic susceptibility factors for diseases. Pharmacogenetics encompasses the study of genetic factors and gene-environment interactions that influence drug delivery, bio-availability, metabolism, clearance, and toxicity. Research in Pharmacogenetics is at the interface of experimental pharmacology, genomics, epidemiology and bioinformatics and therefore draws on collaborative expertise in many areas of research at the University of Pennsylvania. Areas of research focus on the relationship between genotype and disease phenotype and the response to therapy as well as on population based polymorphisms in disease related genes and inheritance of predisposing genetic factors. Various models are being established using transgenic animals to investigate drug-genotype interactions as a function of environment or in the context of other disease causing genetic factors. Expression profiling is being used to track the natural progression of pathology in disease and to monitor responses to drug therapy while various approaches are being developed to determine the impact of genetic factors on planning, executing, and interpreting clinical trials. Students use the flexibility of the training program in the Graduate Group to supplement core courses with specialized courses and training in areas selected to complement the area of their eventual thesis research.

Pharmacological Chemistry

Understanding the chemistry of molecular recognition between drugs and their targets (receptors, ion-channels, enzymes and nucleic acids) is a primary focus of research and training in Pharmacological Chemistry. Approaches being used include protein engineering, rational and irrational approaches to drug design, and identifying novel pathways of drug and xenobiotic metabolism and chemical transformations involved in these pathways. Research and training in structural aspects of Pharmacological Chemistry involve elucidating 3-dimensional structures of drugs bound to their targets, identifying pharmacophores (atomic arrangement of functional groups in a ligand) essential for drug activity, the structure and folding of drugs and their targets in lipid membranes, and computer-modeling to define ligand binding sites in drug targets. Other research and training focuses on the chemistry and enzymology of drug targets, activation of carcinogens, synthesis of specific receptor ligands and inhibitors, and engineering proteins with altered/mutated specificity and function. Techniques and resources available include: steady-state and stopped-flow absorbance/fluorescence spectrometers; a 32-node computational chemistry cluster; a computer graphics laboratory; x-ray crystallography; PET-imaging; internal reflection infrared spectroscopy; and state-of-the art analytical instrumentation including mass spectrometry and HPLC systems with EC, UV/Vis and diode-array detection capabilities. Three graduate level courses in Pharmacological Chemistry have been developed to supplement the core pharmacology curriculum.

Targeted Therapeutics

Targeting therapeutic and imaging agents to desired tissues, cells and sub-cellular compartments is one of the biomedical Holy Grails. Such a targeting of chemical drugs and more novel biotherapeutics, pro-drugs and multimodal agents holds a promise to improve diagnosis, prophylaxis and treatment of a plethora of diseases – inflammation, infections, cancer, cardiovascular, pulmonary, metabolic, neurological, genetic and other maladies. Targeted therapeutics provide spatiotemporal and mechanistic precision of imaging and therapeutic interventions, with control over timing, duration, localization and amplitude of the desirable effects, along with alleviation of side effects, doses and inconvenient treatment regimens. Further, targeted therapeutics provide unique means to test the role of specific molecules, pathways and cells in animal models of pathology. This highly translational area of research offers a slew of both hypothesis-driven and technology-driving paradigms, projects and approaches.

Goals and approaches of targeted therapeutics include identification of site-specific therapeutic targets and molecular markers of pathologies, molecular and supramolecular design of affinity moieties and nanocarriers for targeted delivery of therapeutic and imaging agents, studies of sub-cellular trafficking and effects of targeted therapeutics and ultimate translation of these novel compounds into industrial development and clinical domain, via characterization of their pharmacokinetics, effects and toxicity. Studies in this exciting and truly interdisciplinary area of research transcend disciplines of pharmacology and pharmaceutical sciences, bioengineering and biotechnology, cell biology and immunology, radiology and many basic and clinical disciplines.

Targeted Therapeutics houses more than ten PGG faculty members from the Schools of Medicine, Engineering and CHOP and offers a rich and diverse training and research environment. It is closely associated with its counterparts at ITMAT and CTSA and features activities including the weekly Journal Club, The Provost’s Interdisciplinary Seminar Series in Targeted Therapeutics and Drug Delivery and monthly Work-in-Progress presentations of the participating Principal Investigators.