ingest cdrApp 2017-07-06T12:57:36.195Z ccd64451-f0fc-4a42-94ad-226f4041fa4f modifyDatastreamByValue RELS-EXT cdrApp 2017-07-06T13:16:47.259Z Setting exclusive relation modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2017-09-08T14:33:34.181Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-01-04T20:10:42.426Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-01-25T06:08:22.181Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-01-27T06:33:41.295Z modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-02-16T05:27:15.189Z Setting exclusive relation addDatastream MD_TECHNICAL fedoraAdmin 2018-02-16T05:27:26.262Z Adding technical metadata derived by FITS addDatastream MD_FULL_TEXT fedoraAdmin 2018-02-16T05:27:51.379Z Adding full text metadata extracted by Apache Tika modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-02-16T05:28:13.572Z Setting exclusive relation modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-03-14T02:47:27.485Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-05-17T14:32:37.603Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-11T01:15:50.449Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-17T21:21:21.310Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-08-08T20:40:00.442Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-08-15T17:49:18.086Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-21T18:14:28.507Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-26T21:30:50.652Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-10-11T22:04:52.190Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-03-20T15:35:45.337Z John Bohnsack Author Department of Pharmacology School of Medicine EPIGENETIC CONTROL OF GABAA-R EXPRESSION BY ETHANOL Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is -aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. Spring 2017 2017 Pharmacology Neurosciences Addiction, Alcohol, CRISPR Cas9, Epigenetics, GABA Receptors eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text John Bohnsack Author Department of Pharmacology School of Medicine EPIGENETIC CONTROL OF GABAA-R EXPRESSION BY ETHANOL Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. Spring 2017 2017 Pharmacology Neurosciences Addiction, Alcohol, CRISPR Cas9, Epigenetics, GABA Receptors eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text John Bohnsack Author Department of Pharmacology School of Medicine Epigenetic control of GABAA-R expression by ethanol Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. Spring 2017 2017 Pharmacology Neurosciences Addiction, Alcohol, CRISPR Cas9, Epigenetics, GABA Receptors eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text John Bohnsack Creator Department of Pharmacology School of Medicine Epigenetic control of GABAA-R expression by ethanol Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. Spring 2017 2017 Pharmacology Neurosciences Addiction, Alcohol, CRISPR Cas9, Epigenetics, GABA Receptors eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text John Bohnsack Creator Department of Pharmacology School of Medicine Epigenetic control of GABAA-R expression by ethanol Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. Spring 2017 2017 Pharmacology Neurosciences Addiction, Alcohol, CRISPR Cas9, Epigenetics, GABA Receptors eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text John Bohnsack Creator Department of Pharmacology School of Medicine Epigenetic control of GABAA-R expression by ethanol Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. 2017-05 2017 Pharmacology Neurosciences Addiction, Alcohol, CRISPR Cas9, Epigenetics, GABA Receptors eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text John Bohnsack Creator Department of Pharmacology School of Medicine Epigenetic control of GABAA-R expression by ethanol Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. 2017 Pharmacology Neurosciences Addiction, Alcohol, CRISPR Cas9, Epigenetics, GABA Receptors eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text 2017-05 John Bohnsack Creator Department of Pharmacology School of Medicine Epigenetic control of GABAA-R expression by ethanol Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. 2017 Pharmacology Neurosciences Addiction, Alcohol, CRISPR Cas9, Epigenetics, GABA Receptors eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text 2017-05 John Bohnsack Creator Department of Pharmacology School of Medicine Epigenetic control of GABAA-R expression by ethanol Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. 2017 Pharmacology Neurosciences Addiction, Alcohol, CRISPR Cas9, Epigenetics, GABA Receptors eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text 2017-05 John Bohnsack Creator Department of Pharmacology School of Medicine Epigenetic control of GABAA-R expression by ethanol Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. 2017 Pharmacology Neurosciences Addiction, Alcohol, CRISPR Cas9, Epigenetics, GABA Receptors eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde W. Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text 2017-05 John Bohnsack Creator Department of Pharmacology School of Medicine Epigenetic control of GABAA-R expression by ethanol Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. 2017 Pharmacology Neurosciences Addiction, Alcohol, CRISPR Cas9, Epigenetics, GABA Receptors eng Doctor of Philosophy Dissertation Pharmacology A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde W. Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text 2017-05 University of North Carolina at Chapel Hill Degree granting institution John Bohnsack Creator Department of Pharmacology School of Medicine Epigenetic control of GABAA-R expression by ethanol Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. 2017 Pharmacology Neurosciences Addiction, Alcohol, CRISPR Cas9, Epigenetics, GABA Receptors eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text 2017-05 John Bohnsack Creator Department of Pharmacology School of Medicine Epigenetic control of GABAA-R expression by ethanol Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. 2017 Pharmacology Neurosciences Addiction; Alcohol; CRISPR Cas9; Epigenetics; GABA Receptors eng Doctor of Philosophy Dissertation Pharmacology A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde W. Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text 2017-05 University of North Carolina at Chapel Hill Degree granting institution John Bohnsack Creator Department of Pharmacology School of Medicine Epigenetic control of GABAA-R expression by ethanol Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. 2017 Pharmacology Neurosciences Addiction, Alcohol, CRISPR Cas9, Epigenetics, GABA Receptors eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmacology A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde W. Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text 2017-05 John Bohnsack Creator Department of Pharmacology School of Medicine Epigenetic control of GABAA-R expression by ethanol Alcohol use disorders (AUDs) are a chronic debilitating psychiatric disease that account for one in ten preventable deaths and $223.5 billion dollars in lost economic costs in the United States alone. Despite the considerable social, psychological, and economic costs of AUDs, there exist few effective treatment options available. One reason for this may be that the molecular underpinnings that drive alcohol dependence and the development of alcohol use disorders are still poorly understood. A major component of the development of withdrawal and dependence symptoms is γ-aminobutyric acid A (GABAA) hypofunction that occur through the downregulation of GABAA receptors. This work presents evidence showing that GABAA-R downregulation occurs through an epigenetic deacetylation mechanism that is mediated by histone deacetylase 2 and 3. Importantly, this downregulation can be prevented by the administration of histone deacetylase inhibitors, genetic strategies targeting histone deacetylase 2 and 3, and epigenetic strategies that target Gabra1 promoters using the CRISPR-Cas9 system. The results presented herein demonstrate a novel mechanism for the development of alcohol dependence and other disorders where GABAA-Rs are dysregulated and may inform the development of new therapeutic strategies for the treatment thereof. 2017 Pharmacology Neurosciences Addiction; Alcohol; CRISPR Cas9; Epigenetics; GABA Receptors eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution A. Leslie Morrow Thesis advisor Fulton Crews Thesis advisor Clyde W. Hodge Thesis advisor Juan Song Thesis advisor Thomas Kash Thesis advisor text 2017-05 Bohnsack_unc_0153D_16851.pdf uuid:80f55296-ac6a-4627-a463-d0c79ed19ff0 2017-04-24T19:31:50Z proquest 2019-07-06T00:00:00 yes application/pdf 17439385