Research Projects: Lukas-Whiteaker Lab
The research at the Laboratory of Neurochemistry focuses on nicotinic acetylcholine receptors (nAChR). These dendritic structures are critical to chemical signaling and electrical wiring in the brain and body and therefore play a role in regulating mood and emotion, attention and cognition, autonomic homeostasis and movements, and a variety of neuropsychiatric diseases. These receptors normally respond to the acetylcholine, a neurotransmitter, which is released by activated nerve (or other) cells.
Nicotinic receptors also are targets of tobacco-based nicotine and therefore are relevant to tobacco-related diseases. For example, patients with Parkinson’s and Alzheimer’s diseases have fewer nAChR, perhaps indicating roles in the origin and progression of these diseases or in protection from neurodegeneration. Nicotinic receptors are also implicated in neuromuscular disorders. They have been identified as targets for autoimmune responses or gene mutations causing myasthenia gravis and in the dystrophin-related complex targeted in muscular dystrophy. Mutations in nicotinic receptors also are associated with inherited forms of epilepsy.
These receptors likely play critical roles in nicotine dependence, which ultimately is the cause of tobacco-related diseases in general. The Neurochemistry Laboratory has also proposed that in some individuals tobacco use represents a form of nicotine self-medication to correct chemical and electrical signaling deficits associated with emotional and/or cognitive difficulties. Indeed, individuals with mental health problems such as depression, anxiety, and attention deficit disorder are at higher risk of developing nicotine dependence. Approximately 40% of the mentally ill, including as many as 90% of schizophrenics, are smokers.
There is also evidence of drug codependence: Ninety percent of alcoholics are also smokers. Nicotinic receptors are the target of much pharmaceutical research, partly because nicotine can improve attention and/or cognition in patients with Parkinson’s, Alzheimer’s, and attention deficit disorder, improve mood in depressed individuals, and reduce the frequency of tics in Tourette’s patients. However, there are certain developmental periods (especially during perinatal periods, adolescence, and young adulthood) when abnormal signaling through nicotinic receptors mediated by nicotine can influence [AU: good? Bad?] many of the body’s organ systems.
The Neurochemistry Laboratory is investigating several topics related to nAChRs. Our specific areas of focus are as follows:
- Identifying and classifying the diverse family of nicotinic receptors, each of which is defined by their constituent building blocks or subunits. This research seeks to identify subunits and receptor subtypes in different tissues and organ systems, exploit tumor cell lines to naturally manufacture nicotinic receptors like those found in normal tissue, and create genetically-engineered cell lines optimized for examining suspected or known features of nicotinic receptors to exist.
- Tapping the disciplines of molecular and cellular biology, immunology, protein chemistry, pharmacology, and electrophysiology to provide the most comprehensive description possible of nicotinic receptors under study. For example, identification of differences in the ability of different nicotinic receptor subtypes to interact with specific drugs is used not only to distinguish between different receptor subtypes, but also to discover new drugs that are selective or specific in their preference for a given receptor subtype. This portends an opportunity to develop a nicotine-derived drug that could elevate mood by acting at one receptor subtype without causing nicotine dependence through interactions with receptors in the pleasure-reward center of the brain.
- Working to define which of the seventeen subunits identified to date combine to make unique receptor subtypes. Once a subtype has been identified, its features need to be characterized. Studies of the effect of chronic nicotine exposure on receptor numbers and function are underway to define how the brain changes in response to that exposure. Fundamental features of nicotinic receptors in the pleasure-reward, emotional, and attention centers are being investigated.
- Extending this research to cell lines other than muscle and nerve cells. Evidence suggests that nicotinic receptors are present in the vasculature of many organs, including the brain, where they contribute to the blood-brain barrier and influence cytotoxic and vasogenic phases of edema during stroke. Other studies are exploring the role that nicotinic receptors play in nervous and immune interactions and in the lung and in lung tumor growth. Bone formation and reproductive organ function also seem to be influenced by nicotine exposure, implying that nicotinic receptors are found on the relevant cell types in those bodily systems as well.
- Evaluating nicotinic receptors as models to be used for the development of sophisticated tools for proteomics research. Genetically engineered cells and site-directed mutagenesis studies are being used both to define structural and functional relationships for the many diverse roles of nicotinic receptors and to serve as a model of several genetically based neurological diseases. They are also used in studies to define the functional consequences of such mutations.
- Elucidating nicotinic receptor subunit gene polymorphisms that may prove to be indicators—and that can be assessed through gene array techniques—of susceptibility to neurological or psychiatric disease, vulnerability to nicotine dependence, and the likelihood of success in smoking cessation therapy. Other studies have revealed changes in gene activity induced by nicotine exposure, possibly revealing how some effects of nicotine exposure can be long-lasting, but also revealing important targets for normal signaling through nicotinic receptors.
- Demonstrated recognition for our work nationally and internationally, past or current funded studies and/or studies leading to published contributions involve dozens of collaborating scientists at the University of Arizona, Arizona State University, Sun Health Research Institute, several biotechnology companies in the state, nationally, or internationally; and at many other institutions in the country and worldwide. We have collaborators in Phoenix, Tempe, Tucson, Scottsdale and Sun City; Ann Arbor, Baltimore, Bethesda, Boston, Denver, Durham, Gainesville, Houston, Ithaca, Kalamazoo, Lubbock, Los Angeles, Memphis, Palo Alto, Philadelphia, Raleigh, Richmond, Salt Lake City, San Diego, St. Louis, Tampa and Winston-Salem; Bahia Blanca, Bath, Edinburgh, Edmonton, Geneva, Heidelberg, Montpellier, Oxford, Paris and San Juan
- Contributed to demonstration of nicotinic acetylcholine receptor diversity
- Identified or created natural or genetically engineered cell models for nicotinic receptor research
- Contributed to basic pharmacological and structural characterization of nicotinic receptors
- Identified genes regulated by nicotinic receptor activity using gene chip microarrays
- Defined the effects of smoking and chronic nicotine exposure on nicotinic receptor function at the molecular level