2009 — 2010 |
Barrett, Ruth M |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Regulation of Transcription by Chromatin Modifying Enzymes in Extinction Learning @ University of California-Irvine
DESCRIPTION (provided by applicant): Extinction is an experience-dependent process by which a previously learned behavioral response is reduced. It is currently in use as a form of behavioral therapy for human disorders including posttraumatic stress and anxiety disorders. Drugs that enhance extinction have been shown to be effective at enhancing extinction-based behavioral therapy in clinical trials. Extinction has been studied extensively at the behavioral level, but its molecular mechanisms have been investigated only recently. Based on what is known about original associative learning and its similarity to extinction, it is possible that transcription, which is necessary for original associative learning, is also necessary for extinction learning. Recently, it has become clear that regulation of gene transcription necessary for long-term memory formation involves the concerted action of multiple transcription factors and cofactors that interact with chromatin, a protein complex that packages DNA. Chromatin modification via histone acetylation (a form of epigenetic gene regulation) is emerging as a major molecular pathway involved in the transcriptional regulation of gene expression required for synaptic plasticity and memory storage. The primary goal of this proposal incorporates behavioral, pharmacological, and molecular approaches to examine the role of histone acetylating/deacetyling enzymes that may underlie extinction processes. The first aim of this research proposal is to determine the role of CREB-binding protein (CBP), a histone acetyltransferase known to be involved in associative learning, in the acquisition of extinction. The second aim is to determine the effects of histone deacetylase inhibitors, which increase histone acetylation and have been shown to enhance associative learning, on the acquisition and persistence of extinction. The focus of the third aim is to determine how chromatin modifying enzymes (HDACs and CBP) regulate transcription of Nr4a genes during extinction. My research plan focuses on two important aspects of extinction: development and persistence. By understanding the molecular and epigenetic mechanisms of extinction, we can recommend techniques to reduce the duration of human extinction therapy for disorders such as post-traumatic stress disorder, phobias and anxiety disorders, which has the potential to greatly impact the people who complete a treatment program. By examining the persistence of extinction, we can determine whether these treatments cause lasting changes, thus reducing relapse. Furthermore, histone deacetylase inhibitors are FDA approved drugs, which significantly increases the potential translational value of this research.
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1 |
2013 — 2014 |
Barrett, Ruth M |
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. |
Identification of Neuronal Microrna Targets @ Oregon Health & Science University
DESCRIPTION (provided by applicant): The critical and diverse roles of microRNAs in the brain are continuing to be discovered. To date, microRNAs have been implicated in neurogenesis, neurodevelopment, synaptic plasticity, and neuropsychiatric disorders. To fully understand how microRNAs carry out these functions, both in normal and pathological states, their mRNA targets must be identified and characterized. This project takes advantage of the RISC-trap assay, an excellent tool to address the roles of microRNAs in neurons. RISC-trap utilizes a dominant negative component of the RNAi-Induced Silencing Complex (RISC) - a central component in the microRNA pathway that is the bridge between microRNAs and their targets- to identify targets of individual microRNAs. This project will use RISC-trap to identify a comprehensive set of mRNAs targeted by miR-132, involved in neuronal maturation, mature function, and disease states, and miR-124, demonstrated to promote neural differentiation and recently shown to regulate plasticity. Neuron-specific microRNA targets may be in one of two categories. They may encode transcripts, such as synaptic components, that have neural-specific functions. Alternatively, and of particular interest, will be transcripts that are expressd in both neurons and HEK cells, but where the miR-132 or miR-124 interactions occur exclusively in neurons-these interactions may require the activities of specific RNA-binding proteins. Identifying targets specific to neurons will advance understanding of the mechanisms used by microRNAs in neurons. This global target-identification approach will be complemented by examining the regulation of a novel miR-132 target, ARHGEF11, which was identified in RISC-trap screen of HEK cells, and is also known to contribute to neuronal cell signaling. This PDZ-containing protein is interesting because it has been shown to activate Rho signaling and suppress neurite outgrowth. Additionally, ARHGEF11, like miR-132, has been linked to schizophrenia. This project takes advantage of both miR-132 knockout mice and conditional knockout mice, which provide the ability to target excision of the miR-132 locus in the adult newborn neurons of the conditional knockout mouse to examine how ARHGEF11 is regulated by miR-132 in these cells. A thorough investigation miR-132 and miR-124 targets will lead to a deeper understanding of the mechanism of action of these microRNAs and may reveal drug targets for neurodevelopmental disorders and potentially disorders of the adult nervous system.
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0.945 |