Development of in vivo probes to study the function of TRIP8b in cognition

开发体内探针来研究 TRIP8b 在认知中的功能

• 批准号: 10665810
• 负责人: Dane M Chetkovich
• 金额: $ 82.5万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665810
• 关键词: Address; Animal Model; Arrhythmia; Binding; Biochemical; Biological; Biological Assay; Biology; Biophysics; Brain; Brain region; Cardiac; Cells; Cellular Assay; Characteristics; Chemicals; Chronic; Chronic stress; Cognition; Cognitive; Cognitive deficits; Cyclic Nucleotides; Data; Development; Dorsal; Drug Targeting; Electrophysiology (science); Flow Cytometry; Genetic; Heart; High Prevalence; Hippocampus; Impaired cognition; Impairment; In Vitro; Knock-out; Knowledge; Learning; Long-Term Potentiation; Major Depressive Disorder; Mediating; Memory; Mental Health; Mental disorders; Methods; Molecular; Molecular Target; Mus; Neurons; Nootropic Agents; Pathway interactions; Performance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phenotype; Play; Process; Property; Publishing; Reporting; Risk Factors; Role; Series; Specificity; Surface; Symptoms; Testing; Toxic effect; Translational Research; Validation; Work; analog; cognitive change; cognitive process; common symptom; cyclic-nucleotide gated ion channels; experimental study; high throughput screening; hippocampal atrophy; hippocampal pyramidal neuron; improved; in vivo; inhibitor; insight; interest; mouse model; neuronal excitability; neuropsychiatric disorder; novel; pharmacologic; reduce symptoms; response; scaffold; side effect; small molecule; small molecule inhibitor; social defeat; therapeutic target; therapy design; tool; trafficking; translational medicine; validation studies

Abstract Cognitive dysfunction is a common feature of neuropsychiatric diseases related to chronic stress. These symptoms can be debilitating, and despite the high prevalence of illnesses like Major Depressive Disorder, there are relatively few treatment options. To better address these symptoms, novel molecular targets are needed. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a critical role in regulating excitability in the hippocampus, a brain region critically involved in cognition. To avoid cardiac side effects associated with antagonizing HCN channels (which are also expressed in the heart), our group has focused on TRIP8b, a neuron-specific subunit of HCN channels. In our recently published report (Lyman et al, in press at Science Translational Medicine), we established that chemogenetically disrupting the interaction between TRIP8b and HCN in the dorsal hippocampus is sufficient to rescue impairments in cognition after chronic stress. Combined, these results are consistent with the hypothesis that a small molecule that disrupts the TRIP8b-HCN interaction could rescue the cognitive dysfunction seen after chronic stress. In order to capitalize on this discovery, our group recently executed a high throughput screen to identify small molecule inhibitors of the TRIP8b-HCN interaction. We identified one candidate scaffold which shows promising activity as a TRIP8b inhibitor. This compound series serves as the basis for our current submission in which we propose further medicinal chemistry optimization to develop TRIP8b inhibitors for use as chemical probes in order to study TRIP8b in vivo. In our enclosed preliminary data, we show that our inhibitor potently disrupts the interaction between TRIP8b and HCN in cells with negligible toxicity. This inhibition produces robust effects on Ih, the current mediated by HCN channels both in vivo and in vitro. To expand upon this work, we propose three aims. In Aim 1, we will perform iterative medicinal chemistry optimization to develop compounds with improved potency and pharmaceutical characteristics. Compounds that perform well in our biochemical and biophysical assays will be advanced to cellular assays in Aim 2 in order to determine if they are capable of disrupting the TRIP8b-HCN interaction. In Aim 3 we will utilize our compounds in vivo to study their effect on hippocampal function. Promising compounds will be investigated for their ability to rescue cognitive deficits that result from chronic social defeat, an animal model of chronic stress. These experiments will enable us to develop TRIP8b inhibitors that can be used as chemical probes to study the role of HCN channels in regulating cognitive dysfunction after chronic stress.

抽象的 认知功能障碍是与慢性应激有关的神经精神疾病的常见特征。这些 症状可能会使人衰弱，尽管疾病患病率很高，例如重度抑郁症，但 治疗选择相对较少。为了更好地解决这些症状，新的分子靶标是 需要。超极化激活的环状核苷酸门控（HCN）通道在调节中起关键作用 海马的兴奋性，这是一个与认知非常重要的大脑区域。避免心脏副作用 与对抗HCN通道（也在心脏中表达）有关，我们的小组聚焦 在Trip8b上，HCN通道的神经元特异性亚基。在我们最近发表的报告中（Lyman等人，in 在科学翻译医学上播放），我们确定化学上会破坏相互作用 在背部海马中的Trip8b和HCN之间足以挽救认知障碍。 慢性应激。这些结果结合在一起，与一个小分子破坏的假设一致 TRIP8B-HCN相互作用可以挽救慢性应激后看到的认知功能障碍。为了 利用这一发现，我们的小组最近执行了一个高吞吐量屏幕以识别小分子 TRIP8B-HCN相互作用的抑制剂。我们确定了一个候选脚手架，显示出有希望的活动 作为Trip8b抑制剂。这个化合物系列是我们当前提交的基础 提出进一步的药物化学优化，以开发TRIP8B抑制剂作为化学探针 为了在体内研究Trip8b。在我们封闭的初步数据中，我们表明我们的抑制剂有效中断 Trip8b和HCN之间的相互作用在具有微不足道的毒性细胞中。这种抑制会产生强大的 对IH的影响，HCN通道在体内和体外介导的电流。为了扩大这项工作，我们 提出三个目标。在AIM 1中，我们将进行迭代药物化学优化以开发 具有提高效力和药物特性的化合物。在我们的表现良好的化合物 生化和生物物理测定将在AIM 2中进行细胞测定，以确定它们是否是否 能够破坏TRIP8B-HCN相互作用。在AIM 3中，我们将利用我们的化合物在体内学习 它们对海马功能的影响。有希望的化合物将因其营救能力而进行调查 慢性社会失败导致的认知缺陷，这是一种慢性压力的动物模型。这些实验 将使我们能够开发可用作化学探针的TRIP8B抑制剂来研究HCN的作用 慢性应激后调节认知功能障碍的通道。