The protein mTOR (or mammalian Target Of Rapamycin) regulates cell growth, proliferation, motility, energy status, and survival. In the brain, mTOR activity is important for learning and memory. Dr. Raab-Graham has shown that mTOR suppresses the local translation of the voltage-gated potassium channel Kv1.1. Many voltage-gated ion channels are important for proper neuronal communication. How their expression is regulated during learning and memory is unknown. With a strong background in ion channels, cell biology and biochemistry her lab will identify the physiological and molecular mechanism for mTOR suppression of Kv1.1. She hypothesizes that several different types of ion channels are under the local control of mTOR. Discovering how mTOR suppress Kv1.1 translation may lead to identifying a network of functionally related genes that are inhibited by mTOR.
This project provides training for undergraduates, graduates, and postdoctoral students in the multidisciplinary project addressing the molecular, biochemical, and physiological mechanisms of learning and memory, an intrinsic benefit to society. Members of the PI's laboratory participate in the public outreach program, Memory Matters. This event educates the community by engaging them in scientific demonstrations of our research, in a manner designed to educate and inform non-scientists. Through this involvement, future generations of scientists are learning to serve as liaisons between the scientific community and the general public. In addition, this project will help support the development of new technology to detect changes in electrical signaling in neuronal dendrites. This endeavor is part of an international collaboration with scientists in Japan. Furthermore, the academic training ground provided by this project will concentrate on retention of women in science, by encouraging all students to be rigorous scientists, to serve as scientific liaisons, and to learn how to effectively balance the demands of a scientific career with other life obligations.
Intellectual Merit: Our studies have made contributions to both the fields of Molecular Neuroscience and Cell biology. Molecular Neuroscience: Our studies describe how a key protein, mammalian target of rapamycin (mTOR), prevents the expression of a voltage-gate potassium channel, in neuronal processes (dendrites) that recieve information from other nerve cells in the brain. These channels are considered dendritic shock absorbers. Thus, reduced expression of these channels will ensure communication between two neurons. These studies provide a new and novel function of the mTOR protein in neuronal dendrites. Cell Biology: We discovered that messenger RNAs (mRNAs - the intermediate messenger between the gene and resulting functional protein) compete for the binding of RNA-binding proteins, whose abundance is limited. Binding of the RNA-binding protein to a specific mRNA ensures its ability to be made into a protein. We determined RNA-binding proteins favor those mRNAs that have many binding sites over those mRNA with few binding sites. When the mRNAs with many binding sites degrade the RNA-binding protein is free to bind and promote the expression of those mRNAs with few binding sites. In summary, when mTOR activity is low in neuronal dendrites those mRNAs with many binding sites degrade and the potassium channel mRNA that we described above, which has few binding site for RNA-binding proteins to bind to, is made and is likely to reduce the communication between two nerve cells. The findings of these studies have been published in three peer reviewed journals. Three additional manuscripts are under review at peer reviewed journals. We are currently writing a review on how our work fits into the broader context of translational regulation during learning, memory, and disease. Broader Impact: This award has provided training for two postdoctoral students, two graduate students, and approximately 10 undergraduate students.My students participate in the Center for Learning and Memory’s biannual Memory Matters. This event educates the community by engaging them in scientific demonstrations of our research, in a manner designed to relate to non-scientists. Importantly, my students are learning to serve as liaisons between the scientific community and the general public.
