Regulation of transcription by chromatin modifying enzymes in extinction learning

描述(由申请人提供)：灭绝是一个依赖经验的过程，通过这个过程，以前学习到的行为反应会减少。它目前被用作一种行为疗法，用于治疗人类疾病，包括创伤后应激障碍和焦虑症。在临床试验中，增强消退的药物在增强基于消退的行为疗法方面被证明是有效的。灭绝在行为水平上已经得到了广泛的研究，但其分子机制直到最近才被研究。基于对原始联想学习及其与灭绝的相似性的了解，原始联想学习所必需的转录可能也是灭绝学习所必需的。最近，人们已经清楚地发现，长期记忆形成所需的基因转录调控涉及多个转录因子和辅助因子的协同作用，这些转录因子和辅因子与染色质相互作用，染色质是包装DNA的蛋白质复合体。染色质通过组蛋白乙酰化修饰(一种表观遗传基因调控)正在成为参与突触可塑性和记忆存储所需基因表达转录调控的主要分子途径。这项建议的主要目标是结合行为、药理学和分子方法来研究组蛋白乙酰化/去乙酰化酶的作用，这些酶可能是灭绝过程的基础。这项研究建议的第一个目的是确定CREB结合蛋白(CBP)，一种已知参与联想学习的组蛋白乙酰转移酶，在获得灭绝中的作用。第二个目的是确定组蛋白去乙酰酶抑制剂对获得和持续消亡的影响，组蛋白去乙酰酶抑制剂可以促进组蛋白乙酰化，并被证明可以增强联想学习。第三个目标的重点是确定染色质修饰酶(HDACs和CBP)在灭绝过程中如何调节Nr4a基因的转录。我的研究计划集中在灭绝的两个重要方面：发展和持续。通过了解灭绝的分子和表观遗传学机制，我们可以推荐一些技术来缩短人类灭绝疗法的持续时间，以治疗创伤后应激障碍、恐惧症和焦虑症等疾病，这些疾病可能会对完成治疗计划的人产生巨大影响。通过检查灭绝的持久性，我们可以确定这些治疗方法是否会导致持久的变化，从而减少复发。此外，组蛋白脱乙酰酶抑制剂是FDA批准的药物，这显著增加了本研究的潜在翻译价值。

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.