Antidepressants: Signal Transduction and Gene Expression

严重抑郁障碍(MDD)是一种具有广泛社会经济影响的破坏性疾病。虽然 MDD的治疗方法已有近50年的历史，可用的药物并不总是有效的， 需要数周甚至数月的治疗。长期抗抑郁药物治疗的要求(ADT) 为了实现治疗反应，导致了细胞和分子适应是 必填项。我们的研究已经确定了信号转导和基因表达中的关键适应，大多数 值得注意的是，cAMP-CREB和BDNF-ERK级联，我们已经开始确定功能 在行为和细胞水平上对改变的CREB和BDNF的反应，上一个资助期 是有效的，结果有助于MDD和ADT的神经营养假说 激发了大量的临床和临床前研究。下一个资助期的研究重点是 结合扩展这些发现，以及启动新的研究领域，所有这些都是一致的 在NIMH战略计划中，在第一个目标中，我们将使用我们拥有的条件PDE4A突变小鼠 首次为任何PDE4亚型生成，以确定PDE4A是否为新型抗抑郁药的可行靶点 激活cAMP-CREB的药物呈级联反应。我们将利用一系列行为模型，包括 焦虑、绝望、快感缺乏和动机/奖励，以评估这些动物的表型和习俗 用于识别额外下游基因靶点的微阵列。在第二个目标中，我们将使用类似的策略 为了确定MKP-1，一种我们已经发现的在MDD患者中增加的双特异性磷酸酶，是否是一种 开发激活BDNF-ERK级联反应的药物的可行目标。初步研究 证明MKP-1突变小鼠对慢性应激具有抵抗力，这表明MKP-1增加 表达会增加对MDD的易感性。第三个目标将描述额外的神经营养。 MDD细胞和行为模型中的因子调控基因靶点。我们还将描述共同的 控制参与MDD和ADT反应的基因盒的启动子元件，包括 神经可塑性、神经保护和突触功能/形成。 相关性(请参阅说明)： 这些研究将进一步表征ADT作用的潜在机制以及 压力的有害影响和确定新的药物靶点，以开发更快的作用和更多的 有效的药物。

Major depressive disorder (MDD) is a devastating illness with broad socioeconomic effects. Although treatments for MDD have been available for nearly 50 years, available drugs are not always effective and require weeks or even months of treatment. The requirement for long-term antidepressant treatment (ADT) to achieve a therapeutic response has lead to the hypothesis that cellular and molecular adaptations are required. Our studies have characterized key adaptations in signal transduction and gene expression, most notably the cAMP-CREB and BDNF-ERK cascades, and we have begun to determine the functional responses at the behavioral and cellular levels to altered CREB and BDNF, The previous funding period has been productive and the results have contributed to a neurotrophic hypothesis of MDD and ADT that has stimulated a large body of clinical and preclinical studies. The research focus for the next funding period is a combination of extending these findings, as well as initiating new research areas, all of which are consistent with the NIMH Strategic Plan, In the first aim we will use conditional PDE4A mutant mice that we have generated, the first for any PDE4 subtype, to determine if PDE4A is a viable target for novel antidepressant medications that activate the cAMP-CREB cascade. We will utilize a battery of behavioral models, including anxiety, despair, anhedonia, and motivation/reward to assess the phenotype of these animals, and custom microarrays to identify additional downstream gene targets. In the second aim we will use a similar strategy to determine if MKP-1, a dual specificity phosphatase that we have found is increased in MDD patients, is a viable target for development of drugs that activate the BDNF-ERK cascade. Preliminary studies demonstrate that MKP-1 mutant mice are resistant to chronic stress, suggesting that increased MKP-1 expression would increase susceptibility to MDD. The third aim will characterize additional neurotrophic factor regulated gene targets in cellular and behavioral models of MDD. We will also characterize common promoter elements that control cassettes of genes involved in MDD and ADT response, including neuroplasticity, neuroprotection, and synaptic function/formation. RELEVANCE (See Instructions): These studies will further characterize the mechanisms underlying the action of ADT as well as the deleterious effects of stress and identify novel drug targets for the development of faster acting and more efficacious medications.