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Research | Core Facilities | Patient Studies | Tech Transfer | Seminars | Intranet | Careers | Search | Contact Us | Ways To Give HOME |
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More about Dr. Miller 101 Genetic Models of Disease Research Program
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Research Interests C. elegans researchers can identify the components of this Synaptic Signaling Network through forward genetic screens centered around easily recognizable phenotypes that affect locomotion, egg laying, and growth on a pesticide called aldicarb. Loss of function mutations in positive regulators tend to cause paralysis or strongly decreased rates of locomotion and egg laying as well as resistance to aldicarb, while loss of function mutations in negative regulators tend to cause hyperactive behaviors. Using large forward genetic screens, our lab and several others have uncovered the three major Ga pathways that control synaptic activity to produce the C. elegans locomotion behavior. In this network, a core pathway controlled by the heterotrimeric G protein Gaq drives locomotion by a mechanism that ultimately impinges on the proteins that mediate synaptic vesicle fusion. A second pathway, controlled by Gao, inhibits the Gaq pathway to negatively regulate locomotion and synaptic activity. The third pathway, controlled by Gas, produces the small signaling molecule cAMP and integrates with the Gaq and Gao pathways to drive locomotion by a poorly understood mechanism. One of the exciting things about this molecular circuit is that its components are all highly conserved in vertebrates, but the redundancy that often complicates analysis in vertebrates is largely lacking. However, there are predicted missing components in each pathway, and there are major gaps in our understanding of exactly how these pathways integrate to control synaptic activity and produce behaviors. These missing components and gaps are amenable to forward genetic investigation, which is a major focus of my lab. Over the past two years we have discovered a specific and interesting connection between a protein that regulates dense core vesicle release and the Gas pathway, we have filled in a missing component of the Gas pathway that is required for learning and memory in flies and has major clinical relevance to human disorders such as depression and schizophrenia, we have found the missing Gaq effector pathway and showed that, in the broad context of Gaq signaling in living animals, it is even more important than the canonical PLCb pathway, and we have discovered the C. elegans light response and the novel light receptor and unusual neurons that mediate it. In all but one of these discoveries, we used unbiased forward genetic screens to let the animal show us the important signaling pathways that animate its life. The pathways of the Synaptic Signaling Network are found in all animals, from worms to humans. Given their high level of conservation, these are probably the same basic pathways that help humans think, remember, and learn. Because these are the core signaling pathways that drive synaptic activity, our work has potential relevance to human neurological disorders such as depression and bipolar disorder, ADHD, sleep disorders, learning and memory disorders, and schizophrenia. The forward genetic approaches that we use often reveal novel connections and molecules that would be missed by other strategies. For example, past forward genetic studies of this network have yielded novel synaptic signaling proteins that are conserved in humans, such as UNC-13 (a synaptic vesicle priming protein), UNC-31 (a dense core vesicle priming protein), EGL-10 (a GAP for Ga proteins), RIC-8 (a GEF for Ga proteins), and UNC-73 (the Gaq effector Trio RhoGEF). Finding these novel connections enriches our understanding of the relationship between synaptic function and behavior and provides new potential drug targets for treating human neurological disorders. Joined OMRF Scientific Staff in 1993. Mailing Address
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