2010 — 2011 |
Korb, Erica Megan |
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 and Function of Arc in the Nucleus @ University of California, San Francisco
DESCRIPTION (provided by applicant): The molecular basis of learning and memory is the modification of neuronal synapses in response to electrical activity, a process termed synaptic plasticity. There are two phases of memory formation. Short-term memory results from modifications of preexisting proteins that change synaptic efficacy, while long-term memory formation requires new gene transcription to stabilize these changes. The activity-regulated cytoskeletal protein Arc is the only protein known to be specifically required for long-term memory formation. In Arc knock- out (KO) mice, short-term learning is not affected, but consolidation and maintenance of memory is lost. Arc is also the only known activity-induced gene for which the mRNA transcript is transported specifically to the site of stimulation. Arc is then locally translated in neuronal dendrites and regulates synaptic strength. This allows it to modify synaptic functions in a way that correlates both temporally and spatially with its inducing stimulus. Interestingly, Arc protein is also highly enriched in the nucleus and activity causes an increase in Arc protein within the nucleus. In the nucleus, Arc associates with promyelocytic leukemia tumor suppressor protein nuclear bodies (PML-NBs), which typically regulate transcription. As long-term memory formation requires transcription and is lost in Arc KO mice, Arc might contribute to transcriptional regulation within the nucleus. This finding, combined with the local translation of Arc at activated synapses, might help to explain how a neuron with thousands of synapses and only one nucleus stores information in a manner that is both synapse-specific and dependent on nuclear processes, such as new gene expression. This proposal aims to determine if the activity-induced Arc localization to the nucleus functions as a mechanism to regulate new gene transcription in long-term memory formation. The proposed experiments will clarify the regulation and function of Arc in the nucleus with the goal of elucidating the molecular basis for the consolidation of new memories. This work will ultimately be important not only in our understanding of the molecular processes behind normal memory storage but also will shed light on the processes that are disrupted in neurological disease that affect memory formation and consolidation. Specific Aim 1: To determine if nuclear Arc regulates total AMPAR levels through transcriptional repression. Specific Aim 2: To determine if Arc increases PML-NBs in an activity-dependent manner as a means of regulating transcription. Specific Aim 3: To elucidate the mechanism of Arc nuclear export. PUBLIC HEALTH RELEVANCE: Memories are formed when neurons change the strength of their connections, yet the underlying mechanisms required for these changes are not fully understood. Elucidating the cellular mechanisms behind memory formation is critical to understanding the memory loss and dysfunction that occurs in neurological diseases. This proposal aims to clarify how neurons for long term memories through investigating the function and regulation of the protein Arc which is required for this process.
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1 |
2014 — 2015 |
Korb, Erica Megan |
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. |
The Role of the Epigenetic Regulator Brd4 in Neuronal Function and Autism
DESCRIPTION (provided by applicant): We propose to examine the role of epigenetics in neuronal function and autism. Our aim is to improve our understanding of chromatin regulation in brain by focusing on epigenetic regulations that are implicated in autism and other aspects of neurological function but have never been investigated in the context of the nervous system. Autism spectrum disorders (ASD) are neurodevelopmental syndromes characterized by impairments in socialization, communication and behavior that affect approximately 1 in 100 children. Despite the high prevalence of ASD, the mechanisms resulting in neuronal dysfunction are poorly understood. Interestingly, recent advances in the field suggest there is a link between autism and epigenetic regulation. Multiple lines of evidence described in this proposal implicate the epigenetic regulator and chromatin- associated protein Brd4 in ASD. Brd4 recruits chromatin-regulating enzymes to target promoters to regulate transcription but has no known function in post-mitotic neurons. However, links between Brd4 and several neurological disorders as well as the preliminary data we describe in this proposal strongly suggest it is critical to neuronal function. We will examine the regulation and function of Brd4 in brain, both i normal neurons and in a well-established model of autism. We hypothesize that Brd4 regulates important aspects of neuronal function such as synaptic strength and that misregulation leads to aberrant patterns of transcription associated with the synaptic abnormalities observed in the FXS model of autism. We seek to test this working hypothesis in two Specific Aims: 1) Investigate the regulation of Brd4 in neurons and 2) Investigate the role of Brd4 in neuronal function and dysfunction. The recent development of small molecule inhibitors that prevent BRD4 function and are used in human clinical settings make this line of research particularly compelling and timely. In Aim 1 we will examine both regulation of the expression of Brd4 and regulation of Brd4-chromatin associations, including how both of these are affected by neuronal activity. In Aim 2, we will examine the role of Brd4 in mediating changes in synaptic strength as well as its role in regulating transcription and the chromatin landscape in neurons. Finally, we will examine how Brd4 affects behavior and will determine if inhibition of Brd4 can alleviate deficits observed in a mouse model of ASD. Ultimately, this proposal has the potential to greatly expand our current understanding of the epigenetic mechanisms influencing normal neuronal function and provide clinically relevant insights into ASDs. Through this work, we aim to promote significant advances in our understanding of chromatin-mediated neuronal function and behavior, as it relates to human psychiatric disease.
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0.943 |
2016 — 2021 |
Korb, Erica Megan |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
The Histone Code of Neuronal Function and Dysfunction
Project Summary A fundamental challenge in the field of neuroscience is understanding the link between environmental signals and the transcriptional response underlying the resulting long term changes in neuronal function. Neurons uniquely require highly dynamic and temporal control of gene activation for processes ranging from memory formation to synapse formation during development. Whether specific genes are ultimately activated is highly dependent on the epigenetic regulation of transcription through the histone proteins that control DNA accessibility and regulate transcription. The importance of this `histone code' or is becoming increasingly appreciated in neuroscience, from its function in memory storage to its involvement in neurological disorders. My goal is to elucidate the histone code that controls the nervous system with the aim of better understanding the regulation of transcription both in normal neurons and in mental and developmental disorders. The research I propose encompasses all aspects of histone regulation and has a strong foundation in the work developed and performed in the Allis laboratory on histone modifications and variants. During the training period, I will continue my work on the role of histone misregulation in neurodevelopmental disorders and the possibility of targeting this to alleviate neuronal dysfunction. I will also investigate the role of a new discovered histone variant linked to the transcriptional response to synaptic activity. Finally, I will begin to investigate the role of histone modifications such as crotonylation that have not yet been examined the context neuronal gene expression but provide the complex transcriptional regulation needed to achieve the varied functions of the nervous system. During this mentored period, I propose to develop and expand on new tools I will use to during the independent phase of the award. In addition, I will learn a combination of computational and genomics techniques and biochemical approaches that will set me apart from the field and provide me with the skills necessary to work at the intersection of epigenetics and neuroscience. With the development of new tools and acquisition of valuable skills that I describe in the training plan of award, I will be a unique position to apply diverse approaches to reveal new insights into the role of histones in regulating transcription of genes critical for neuronal function. This research will allow for the histone code of gene activation to be applied to information storage in the brain, providing new insights into mechanism underlying neuronal function and the epigenetic causes of neurological disorders.
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0.951 |
2021 |
Korb, Erica Megan |
DP2Activity Code Description: To support highly innovative research projects by new investigators in all areas of biomedical and behavioral research. |
The Epigenetic Encoding of Learning and Memory @ University of Pennsylvania
Abstract The nervous system requires tight control of transcription for processes such as learning and memory formation. The field of epigenetics seeks to understand how changes to gene transcription occur in response to environmental cues and external signals such as those that our brains experience during learning. This proposal lies at the intersection of neuroscience and epigenetics, with a particular focus on chromatin biology. Chromatin is the complex of DNA and the histone proteins that wrap up DNA into complex structures, recruit key transcriptional regulators, and in doing so, control gene expression. In recent years, it has become clear that disruptions to chromatin regulation lead to a range of neurological and mental health disorders such as post- traumatic stress disorder (PTSD). However, we have a limited understanding of how chromatin functions in the brain or how its disruption can lead to disease. We will apply the tools and techniques of the epigenetics field to the study of neuronal function. In doing so, we hope to elucidate the molecular mechanisms that allow our brains to perform incredibly complex tasks and how disruption of these mechanisms can lead to neuronal dysfunction. We propose overcome long-standing hurdles in the field using a combination of novel techniques to reveal how the epigenetic landscape encodes the transcriptional changes that underlie memory formation. Specifically, we seek to uncover the transcriptional signature of memory formation and memory maintenance within single neurons in an in vivo context. We then will examine the epigenetic underpinnings of this transcriptional signature and manipulate specific components of the chromatin environment to define their contribution to learning and memory maintenance. First, in order to elucidate the gene program associated with learning, we will use single-nucleus RNA-sequencing in combination with mouse models that label the specific neurons activated during learning. This will allow us to examine the transcriptional programs activated in neurons that form a memory engram compared to their neighboring cells at various times after learning. Next, we will employ a quantitative biochemical approach uniquely available to our group as part of the Epigenetics Institute to characterize the chromatin landscape changes the occur during memory formation, memory maintenance, and reversal learning. Finally, we will modify the chromatin landscape by manipulating specific histone proteins in combination with numerous sequencing approaches to elucidate how chromatin controls learning and the transcriptional program. Employing this novel combination of techniques will allow us to uncover the mechanisms through which the epigenome encodes information within neurons to modify behavior both in the context of normal learning and in the context of maladaptive responses that lead to disorders such as PTSD. If successful, these methods will 1) identify the transcriptional signature that encodes a memory in neurons, 2) map how this signature is encoded by specific epigenetic regulatory mechanisms, and 3) define how the chromatin landscape affects memory formation and contributes to mental health disorders.
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0.951 |