Selective Targeting of Phosphodiesterase 11A Transcription and Catalytic Activit

项目3.环核苷酸(cAMP和cGMP)是细胞内的信号分子，对大脑的发育和功能至关重要。在阿尔茨海默病和精神分裂症患者中，cAMP/cGMP信号的缺陷已经被反复测量。海马体功能障碍(HIPP)--一个调节情感、社会、压力相关和认知行为的大脑区域--也一再被认为与这些神经精神疾病有关。我们相信，选择性地恢复患者HIPP中的环核苷酸信号，而不影响正常脑区的信号，将缓解与神经精神疾病相关的症状，而不会引起不想要的副作用。磷酸二酯酶11A(PDE11A)是一种同时分解cAMP和cGMP的酶。我们最近发现，PDE11A几乎只局限于HIPP。因此，我们假设HIPP中的cAMP/cGMP信号可以通过调节PDE11A的表达和/或功能来选择性地靶向。成年PDE11A基因敲除(KO)小鼠表现出与HIPP功能障碍和神经精神疾病相一致的生化、解剖和行为缺陷。这表明PDE11A功能的增强可能被证明是有疗效的。为了增强特定酶的功能，我们可以增加它的可用性(即表达)或它的催化活性。因此，我们提出了一系列旨在了解PDE11A转录和催化活性的分子机制的目标。在特定的目标1中，我们将确定精神疾病是否与脑中PDE11A转录的变化有关，以及PDE11A启动子中的顺式作用元件是否足以限制PDE11A在健康成人脑中的Hipp表达。在特定的目标2中，我们将确定控制PDE11A启动子活性的信号级联和反式作用蛋白。在具体目标3中，我们将开发小分子PDE11A激活剂，并使用神经精神病学组件在PDE11A野生型和KO小鼠(KOS=阴性对照)上测试它们，以评估疗效和副作用易感性。PDE11A可能能够选择性地恢复受疾病影响的特定脑区的cAMP和cGMP信号，而不影响其他地方的信号。

Project 3. Cyclic nucleotides (cAMP and cGMP) are intracellular signaling molecules that are critical for the development and function ofthe brain. Deficits in cAMP/cGMP signaling have been repeatedly measured in patients with Alzheimer's disease and schizophrenia. Dysfunction ofthe hippocampus (HIPP) - a brain region that modulates affective, social, stress-related, and cognitive behaviors - has also been repeatedly implicated in these neuropsychiatric diseases. We believe that selectively restoring cyclic nucleotide signaling in the HIPP of patients, without affecting signaling in normal brain regions, would relieve neuropsychiatric disease-related symptoms without causing unwanted side effects. Phosphodiesterase 11A (PDE11A) is an enzyme that breaks down both cAMP and cGMP. We have recently discovered that PDE11A is almost exclusively localized to the HIPP. Thus, we hypothesize that cAMP/cGMP signaling in the HIPP can be selectively targeted by modulating PDE11A expression and/or function. Adult PDE11A knockout (KO) mice exhibit biochemical, anatomical, and behavioral deficits that are consistent with HIPP dysfunction and neuropsychiatric disease. This suggests that augmentation of PDE11A function may prove therapeutic. To increase function of a particular enzyme, we can increase either its availability (i.e., expression) or its catalytic activity. As such, we propose a series of aims designed to understand the molecular mechanisms controlling transcription and catalytic activity of PDE11 A. In Specific Aim 1, we will determine if psychiatric disease is associated with changes in PDE11A transcription in brain and if cis-acting elements within the promoter of PDE11A are sufficient to restrict PDE11A mRNA expression to the HIPP in the healthy adult brain. In Specific Aim 2, we will identify the signaling cascades and trans-acting proteins that control PDE11A promoter activity. In Specific Aim 3, we will develop small molecule PDE11A activators and test them in PDE11A wild-type and KO mice (KOs = negative controls) using a neuropsychiatric battery that assesses efficacy and side effect liability. PDE11A may be capable of selectively restoring cAMP and cGMP signaling in a specific brain region impacted by disease, without affecting signaling elsewhere.