Historically, small molecules have been indispensable tools for dissecting nervous system function. However, it has been difficult to discover novel psychotropic compounds and determine the mechanisms by which they affect behavior. Here, I propose to discover new neuroactive compounds that affect dopamine-mediated behaviors in the zebrafish. These studies aim to accelerate the pace of neuroactive drug discovery and provide small-molecule tools for understanding vertebrate behavior. Psychiatric disorders such as depression, anxiety and schizophrenia are widespread and devastating illnesses. Despite the need for improved psychiatric medicines, drug discovery success rates for psychiatric illnesses and other disorders of the nervous system are lower than for other therapeutic areas. The unparalleled complexity of the nervous system undoubtedly contributes to the challenge of identifying novel and effective neuroactive drugs with acceptable toxicity and side effect profiles. To meet the vast unmet need for novel neuroactive drugs, it will be essential to develop new approaches to neuroactive drug discovery. Because the complexity of nervous system is likely to preclude complete mechanistic understanding of disease pathology in the near term, drug discovery approaches that can be effective in the absence of mechanistic understanding will be of particular value. Identifying novel neuroactive chemicals is an important first step toward developing psychiatric medicines. But, lacking a detailed understanding of the biochemical mechanisms that cause psychiatric disease, how can novel neuroactive drugs be discovered? Genetics and pharmacology are the two dominant approaches for understanding molecular signaling pathways in the nervous system. However, traditional pharmacogenetic approaches are heavily biased towards the genome side of systems biology. Genome-wide applications for investigating the effects of single drugs are becoming more common. By contrast, large-scale analyses of how chemicals affect specific genotypes and phenotypes have been much slower to develop. One reason is that phenotype based chemical screens have not been practical or cost-effective using most model organisms. Given the impact of small molecules that were discovered via low throughput and non-systematic approaches, it is likely that systematic behavior-based chemical screening has much to offer. Phenotype based chemical screens in the zebrafish are a non-conventional approach for identifying novel bioactive compounds. It is likely that uncharacterized compounds with valuable neuroactive activity already exist in the wells of modern chemical libraries. However, in vitro assays are too simplistic, and phenotypic assays in mammals too low throughput, to efficiently identify these valuable molecules. Unlike larger vertebrates, zebrafish are small enough to be easily arrayed in the individual wells of a 96-well plate along with chemicals from a chemical library. As a result, behavior-based chemical screens in the zebrafish provide the opportunity to systematically assess how chemicals affect the intact vertebrate nervous system. Dopamine (DA) modifying compounds are important therapeutic drugs and useful research tools. However, only a few bioactive classes of decades-old dopamine-modifying drugs have been identified to date. A main goal of this proposal is to utilize DA-mediated behaviors in the zebrafish as bioassays to identify novel neuroactive drugs and targets. Well-characterized behavioral models of DA signaling have been well- characterized in mice and other model organisms and have been proven to have high predictive validity for identifying known antipsychotic drugs. Thus, novel compounds that modify DA signaling in the zebrafish may also have therapeutic activity for treating the symptoms of schizophrenia, mania and other psychiatric diseases in humans. During the proposed period of mentored research, I aim to gain experience in all aspects of psychoactive drug discovery and development. These skills will enable me to develop my initial findings into an effective and sustainable research program on the leading edge of chemical biology and psychiatric drug discovery. Given the historical roles that behavioral phenotypes and neuroactive drugs have played in our understanding and treatment of mental illness, I expect systematic behavior-based chemical screening in the zebrafish may accelerate the pace neuroactive drug discovery and improve our understanding of the brain and behavior. Eventually, I hope that this work will lead to novel therapeutic approaches for treating mental illness and other neurological disorders.
Historically, small molecules have been powerful tools for dissecting the functions of the nervous system: dopamine (DA) modifying compounds have revolutionized our understanding and treatment of mental illnesses. However, a systematic identification of compounds that modify DA mediated behaviors has not been possible. Here, we propose to utilize newly developed high-throughput behavior based chemical screening strategies in zebrafish to identify and characterize novel DA modifying compounds. These efforts may accelerate the pace of neuroactive drug discovery.
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