Development of siRNA Microinjections to Evaluate Candidate Genes for Behavioral Phenotypes
2006 Seed Grant
Abraham A. Palmer, Ph.D.
The University of Chicago

Dr. Palmer is trying to identify the genetic differences that cause some people to be more sensitive than others to the effects of drugs. We can identify genes that cause differences among mice in their sensitivity to methamphetamine, which is a commonly abused drug that is also similar to drugs used in children to treat attention deficit hyperactivity disorder. We have successfully identified a gene in mice that appears to control sensitivity to this drug, and have found that the same gene also appears to control sensitivity to amphetamine in humans as well. However we do not have good tools to directly test the effects of this gene in mice; our current data is all based on a correlation, which is equivalent to circumstantial evidence. The studies proposed here will allow Dr. Palmer and his lab to prove the relationship between this gene and sensitivity to methamphetamine. They will do this by injecting a small genetic construct into a specific brain region of the mice in order to decrease the expression of the gene that they are interested in. They hypothesize that the response to methamphetamine will be altered in the mice that receive these injections. These studies will help to prove (or disprove) the role of this gene in behavior, and will provide preliminary data that can be used to obtain grants in the future to study this gene and to use this technique to study other genes and their role in a variety of different behaviors.

We know from studies of twins and families that there is a genetic component that increases the risk that some people will become alcoholics or drug abusers. We do not yet know what other differences there are between drug-abuse prone and drug-abuse resistant individuals, but one commonly held hypothesis is that some of the differences between these two groups are in their sensitivity to the pleasant and unpleasant effects of drugs. Dr. Palmer is trying to identify genes that modulate people’s sensitivity to methamphetamine, which is a widely abused drug whose effects are similar to those of cocaine. In this proposal, he seeks to adapt a new technique to the problem area, so that they can quickly test the effects of specific genes on behavior. In the short term, this will allow Dr. Palmer’s lab to test one specific gene; however, once they get the method working in their lab, they hope to use this method to test many more genes in the future. Thus, they may be able to identify genes that put people at risk to become drug abusers, and may also be able to design new drugs to help these people stay off drugs. They also believe that understanding the genes that influence sensitivity to methamphetamine maybe helpful in understanding attention deficit hyperactivity disorder, which is common in children and is currently treated by a drug that is very similar to methamphetamine. Finally, Dr. Palmer and his lab hope that understanding the neurochemical systems involved in the action of this drug may help us to better understand the neurochemical basis of bipolar disorder, since this disease shares common neurochemicals and neurocircuits with methamphetamine.

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Sarah C. Goetz, Ph.D., Duke University
Uncovering a Novel Role for Primary Cilia in Eph/Ephrin Signaling in Neurons
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Erin M. Gibson, Ph.D., Stanford University
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Yvette Fisher, Ph.D., University of California, Berkeley
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Byoung Il Bae, Ph.D., University of Connecticut
Unique Vulnerability of Developing Human Cerebral Cortex to Loss of Centrosomal Protein
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