2001 — 2003 |
Raab-Graham, Kimberly F |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Activity Dependent Expression of Kv 4 2 in Ca-1 Neurons @ University of California San Francisco
The proposed research will focus on the mechanisms by which electrical activity coordinates the surface expression of the A-type potassium channel Kv 4.2 hippocampal neurons. These channels are important in controlling the membrane excitability of the dendrite, a critical factor for normal physiological and pathological processes such as the initiation of long term potentiation (LTP), long term depression (LTD) and seizure. The regulation of the surface expression of Kv 4.2 potassium channels under conditions that promote or block synaptic activity will be addressed by the following specific aims: 1. Determine if a change in synaptic activity effects the surface expression of the A-type potassium channel Kv 4.2 in hippocampal neurons. 2. Determine the molecular mechanism for the change in activity- dependent surface expression of Kv4.2 These experiments are designed to explore how Kv4.2 channels are involved in feedback mechanisms that occur when a neuron undergoes changes in synaptic input during physiological processes such as development, learning, and memory.
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0.943 |
2010 — 2014 |
Raab-Graham, Kimberly |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Posttranscriptional Regulation, a Novel Mechanism For Ion Channel Regulation and Dendritic Excitability @ University of Texas At Austin
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.
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0.915 |
2018 — 2021 |
Raab-Graham, Kimberly Frances |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Mechanism of Hippocampal Network Excitability in a Novel, in Vivo Model of Tuberous Sclerosis Complex @ Wake Forest University Health Sciences
PROJECT SUMMARY Overview: The project focuses on understanding the molecular basis of how disrupted calcium homeostasis leads to disrupted hippocampal network activity that results in maladaptive responses in neurons with TSC deficient signaling. Approximately 33% of children who have autism spectrum disorder (ASD) also have epilepsy. Early childhood seizures can result in compromised synaptic plasticity and cognitive impairment, suggesting that the hippocampus may be vulnerable to changes in network excitability. Despite the importance of this problem, the connection between seizure activity and development of ASD is poorly understood. Mammalian Target of rapamycin (mTOR) is a kinase that regulates protein synthesis and is overactive in many complex brain disorders. In the proposed studies, we focus on a mouse model of ASD, Tuberous Sclerosis Complex (TSC), which is a disorder that results from mutations in either the tsc1 or 2 genes. We propose that deficient TSC signaling leads to overactive mTOR and deficient protein synthesis that manifests as epilepsy and ASD. There is no cure for TSC, treatments are limited, and new therapeutic targets are needed. Our previous work has demonstrated that mTOR activity represses the expression of epilepsy-linked ion channels. The proposed studies extend our work to address the molecular mechanisms underlying hippocampal network hyperexcitability in TSC. We will take a multidisciplinary approach to critically test the prediction that reduced expression of the voltage-gated calcium channel subunit ?2?2 by overactive mTOR signaling in TSC leads to dysregulated calcium homeostasis and aberrant hippocampal network activity. (1) At the molecular level, we ask how ?2?2 expression is regulated by mTOR; (2) at the cellular level, we ask what is ?2?2?s role in dendritic calcium signaling and glutamate receptor recycling in TSC deficient dendrites; and (3) at the network level, we address the effect of ?2?2 in promoting aberrant hippocampal network activity. The proposed work is the first to bridge the gap between underlying molecular/cellular mechanisms and hippocampal network hyperexcitability in TSC, using a novel preclinical model to measure spike and seizure threshold for the first time. The strength of our approach allows us to also test several interventions using our novel optogenetic preclinical model of network activity. Notably, seizure medications do not target only the region of the brain that seizures originate, but can reduce hyperexcitable neurons in other parts of the brain, such as the hippocampus where ASD is tightly linked. Thus, we hypothesize that the hippocampus is vulnerable in children with TSC due to neuronal and network hyperexcitabillity. These studies form the foundation for promising new therapeutic strategies for TSC and other mTOR-related, complex brain disorders, with possible clinical applications.
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0.936 |