Wolfgang Sadée, Dr.rer.nat, Chair
This Department focuses on molecular pharmacology of central nervous system (CNS) agents, cancer chemotherapy and pharmacogenomics. Rene Anand, PhD, Laura Bohn, PhD, Howard Gu, PhD, Norton Neff, PhD, Wolfgang Sadée, Dr.rer.nat, David Saffen, PhD, and Kirk
Mykytyn, PhD, study neurobiology and genetics of drug addiction and related disorders. Insight into the regulation of signaling pathways triggered by drugs of abuse can result in new approaches to treating addiction. Drug discovery in cancer chemotherapy is pursued by Roger Breisewitz, PhD, Paul Blower, PhD, and Sadée. The Department also houses a Program in Pharmacogenomics directed by Sadée and co-directed by Danxin Wang, MD, PhD, with a core laboratory headed by Audrey Papp that features genotyping and tools for discovering genetic variants. The lab supports basic and translational studies on CNS disorders, cardiovascular diseases, cancer, autoimmune disorders, infectious diseases, and therapies.
A Division on Clinical Trials, directed by Glen Apseloff, MD, conducts phase I and II drug studies and trains scientists and clinicians specializing in drug development.
Ongoing Research Programs
- Rene Anand, PhD, and his laboratory team have discovered several nicotinic receptor-associated proteins that modulate their functions. They are studying how these proteins
dysregulate nicotinic receptor functions in the central nervous system. This dysregulation is thought to promote drug addiction to tobacco and contribute to the neuropathologies
of neuropsychiatric disorders such as schizophrenia and neurodevelopmental diseases, including autism spectrum disorders.
- Laura Bohn, PhD, and her laboratory team are developing better therapeutics with limited side effects. They are characterizing herkinorin and chemical derivatives for their signaling properties and their ability to alleviate pain without inducing gastrointestinal and respiratory side effects. They are also studying functional selectivity of serotonin receptor signaling affecting distinct downstream effect, including hallucination; findings may help develop drugs for treating pain as well as neuropsychiatric disorders such as schizophrenia,
insomnia and depression.
- Roger Briesewitz, PhD, and his laboratory team focus on signaling pathways triggered by mutated tyrosine kinases in cancer; they hope to determine the focal point of critical
cancer cell survival factors and target these with novel drugs. Howard Gu, PhD, and co-workers are analyzing cocaine responses in knock-in (KI) mice with a cocaine-resistant
dopamine transporter to dissect the transporter’s roles in mediating cocaine-induced reward, locomotor stimulation, drug sensitization and stereotypic behaviors. They compare their KI mice with wild-type mice in the long-term effects of cocaine on critical transcription factors, which may shed light on mechanisms of cocaine addiction; in addition, they are generating two knock-in mouse lines with a cocaineresistant serotonin transporter or norepinephrine transporter.
- The laboratory team of Kirk Mykytyn, PhD, studies the role of cilia-mediated signaling in development and disease. Their studies involve mouse models of Bardet-Biedl syndrome
(BBS), a human ciliary disorder characterized by obesity, pigmentary retinopathy, polydactyly, kidney and heart defects, hypogenitalism and cognitive deficits. This work will provide insight into the functions of cilia and how ciliary dysfunction leads to complex diseases.
- Norton Neff, PhD, is continuing his work on parkinsonism with a focus on neuroprotective mechanisms. Andrej Rotter, PhD, studies developmental and aging aspects of the cerebellum, focusing on novel tyrosine phosphatase implicated in pathophysiologies. Glen Apseloff, MD, and colleagues in the Division of Clinical Trials are conducting phase I studies, for example, with experimental long-acting local anesthetics; this study, completed in 2007, includes an experimental antiemetic, an experimental diabetes medication and an experimental long-acting local anesthetic.
- Wolfgang Sadée, Dr.rer.nat, Danxin Wang, PhD, and Ohio State’s Pharmacogenomics Program and laboratory focus on polymorphisms in genes encoding drug transporters and
metabolizing enzymes, and on candidate genes involved in cancer, cardiovascular disease and CNS disorders, including addiction. Their goal is to identify and characterize functional polymorphisms that can be used as genetic biomarkers for personalized prevention and prescription; in 2007, three genetic studies identified novel regulatory polymorphisms in the dopamine receptor DRD2 and the angiotensin-converting enzyme ACE, and determined the functional promoter variant in VKORC1, a target of warfarin and a known biomarker clinically used for optimizing warfarin dosages. Subsequent clinical
studies have revealed correlation with cognition, myocardial infarction and drug response in human populations.
- Erick Villamena, PhD, and his laboratory team design and synthesize spin traps that are target-specific within cellular compartments. They apply these new compounds to understand the mechanism and site of radical generation in cellular systems and ultimately to aid in the design of therapeutic strategies to minimize or prevent oxidative damage to vital body organs. Gaining insights into the radical scavenging property of the nitrone spin traps, they also explore the potential use of these compounds as antioxidants for treating neurodegenerative disease and ischemia-reperfusion induced injuries.
Research Accomplishments of 2007
- Rene Anand, PhD, published the first study showing that menthol promotes the physiological effects of nicotine in drug addiction behavior in adolescent but not in adult mice. The implication for humans is that, unlike adults, teenagers may find mentholated cigarettes more addictive than nonmentholated cigarettes.
- Laura Bohn, PhD, described a novel opioid receptor ligand that possesses unique pharmacological characteristics. The compound, termed herkinorin, activates mu opioid receptors but does not recruit beta-arrestins or induce internalization of the receptor. She and her laboratory have also discovered that serotonin promotes serotonin 2A receptor signaling through beta-arrestin2, a finding that is important in designing therapies for drug addiction, pain and schizophrenia (part of this work is published in Proceedings of the National Academy of Sciences).
- Roger Briesewitz, PhD, demonstrated that CDK4/6 constitutes a potential drug target in acute myeloid leukemia, leading to possible discovery and development of therapies for this cancer, which is often refractory to chemotherapy.
- Howard Gu, PhD, published two papers, one in Molecular and Cellular Biochemistry that reported studies on dopamine transporter (DAT) structure and function, and the second in the Journal of Biomedical Central Neuroscience that reported cocaine reward and locomotion stimulation is intact in DAT knockdown mice with only 10 percent of DAT activity. He has engineered mutants of the serotonin transporter and norepinephrine
transporter that are functional but insensitive to cocaine, and he is creating two knock-in mouse lines. His work is instrumental in understanding cocaine effects in a mouse model and could lead to therapies for human addicts.
- Kirk Mykytyn, PhD, reported the development of the first in vitro system for studying primary cilia on neurons. He also identified a prominent marker of neuronal cilia, identified a ciliary localization sequence within G protein-coupled receptors (GPCRs) and used this sequence to identify a ciliary GPCR called melanin-concentrating hormone receptor 1
(Mchr1) that helps regulate feeding behavior. Importantly, he determined that Bardet–Biedl syndrome (BBS) neurons lack ciliary localization of GPCRs, including Mchr1, thus providing the first potential molecular mechanism to link cilia defects with obesity.
- Frederick Villamena, PhD, is developing diagnostic reagents capable of detecting oxidative stress and radical-induced tissue damage using optical sensors. These biomarkers also
have potential as therapies, for example, for congestive heart failure by interrupting the damaging redox reactions involving reactive oxygen and inflammation. He publishes in prestigious chemical journals and, in collaboration with clinicians, in biological and clinical journals.
- Danxin Wang, PhD, and Wolfgang Sadée, Dr.rer.nat, have identified and characterized: the functional polymorphism in VKORC1 (vitamin K epoxide reductase complex subunit
1) that can be used as a genetic biomarker for warfarin dose prediction; a promoter polymorphism in ACE (angiotensin-I converting enzyme) associated with clinical outcomes in hypertension; and polymorphisms in the human dopamine D2 receptor gene that affect mRNA expression, splicing and neuronal activity during working memory (published in
Proceedings of the National Academy of Sciences). A goal is to develop biomarkers to optimize therapies tailored to each patient’s genetic profile.
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