Targeting Postsynaptic Small G-protein Regulators

靶向突触后小 G 蛋白调节因子

• 批准号: 10512614
• 负责人: CHI-HAO LUAN
• 金额: $ 73.35万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-19 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512614
• 关键词: Acute; Autopsy; Award; Behavior; Binding; Biological; Biological Assay; Biological Process; Biology; Brain; Cerebral cortex; Chemicals; Collaborations; Crystallography; Dendritic Spines; Development; Disease; Excitatory Synapse; Family; Fluorescence; Functional disorder; Funding; Genetic; Genetic Diseases; Goals; Guanine Nucleotide Exchange Factors; Guanosine; Guanosine Triphosphate Phosphohydrolases; Hippocampus (Brain); Immunomodulators; Knock-out; Knowledge; Learning; Libraries; Mediating; Memory; Mental disorders; Molecular; Monomeric GTP-Binding Proteins; Neurobiology; Neuronal Plasticity; Neurons; Nucleotides; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Play; Process; Property; Proteins; Rattus; Recombinants; Regulation; Research; Role; Signal Transduction; Site; Specificity; Synapses; Synaptic plasticity; Testing; Therapeutic Intervention; Tissues; Toxic effect; Translating; Triage; United States National Institutes of Health; Validation; Vertebral column; assay development; base; cell type; high throughput screening; inhibitor; knock-down; member; neuronal circuitry; neuropsychiatric disorder; novel; postsynaptic; receptor; screening; small molecule; small molecule inhibitor; tool

ABSTRACT This application aims to discover and validate small-molecule inhibitors of the Rac guanosine-nucleotide exchange factor (GEF) kalirin, a major signal transduction hub in dendritic spines in the cerebral cortex. Our long-term goal is to translate knowledge about dendritic spine plasticity and synaptic small GTPase signaling, into treatments of neuropsychiatric disorders (NPDs). Dendritic spines are the sites of most excitatory synapses in the brain, and play central roles in the development and plasticity of neuronal circuits, and ultimately in learning, memory, and behavior. Conversely, abnormalities in dendritic spines are extensively involved in NPD pathogenesis. Molecular pathways mediated by small GTPases such as Rac, direct upstream activators (GEFs), and their downstream targets are major pathways that govern dendritic spine plasticity. Furthermore, genetic and postmortem studies demonstrate a key role for these pathways in the pathogenesis of NPDs. Kalirin is the most abundant Rac-GEF in dendritic spines in the cerebral cortex and hippocampus, plays central roles in spine plasticity and pathology as shown by knockdown and knockout studies, and has been implicated in NPDs by genetic, postmortem, and functional studies. Hence, in order to study the role of kalirin in cortical plasticity and NPD pathogenesis, and of Rac-GTPase signaling in general, here we aim to develop novel, potent, specific, inhibitors of kalirin with biological activity in neurons. We have established a collaboration between experts in synapse biology and NPDs, high- throughput screening and computational pharmacology, medicinal chemistry, and crystallography, and performed extensive preliminary studies that demonstrate the validity of our hypothesis and the feasibility of our approach. We propose the following Specific Aims: 1) Hit discovery by HTS to identify small molecules binding to kalirin's DHPH domain and inhibiting its GEF activity. 2) Hit validation in cellular and neuronal assays. 3) Characterization of the mechanism of action of hit compounds. 4) Medicinal chemistry optimization of new GEF inhibitors

抽象的 该应用旨在发现并验证 Rac 鸟苷核苷酸的小分子抑制剂 交换因子（GEF）kalirin，大脑皮层树突棘的主要信号转导枢纽。 我们的长期目标是转化有关树突棘可塑性和突触小 GTPase 的知识 信号传导，进入神经精神疾病（NPD）的治疗。树突棘是大多数 大脑中的兴奋性突触，在神经元回路的发育和可塑性中发挥核心作用， 最终影响学习、记忆和行为。相反，树突棘的异常是 广泛参与 NPD 发病机制。由小 GTP 酶（例如 Rac）介导的分子途径， 直接上游激活剂（GEF），其下游靶标是控制树突的主要途径 脊柱的可塑性。此外，遗传和尸检研究证明了这些途径的关键作用 NPD 的发病机制。 Kalirin 是大脑皮层树突棘中最丰富的 Rac-GEF 和海马体，在脊柱可塑性和病理学中发挥着核心作用，如击倒和 基因敲除研究，并通过遗传、尸检和功能研究发现与 NPD 相关。因此， 为了研究 Kalirin 在皮质可塑性和 NPD 发病机制中的作用，以及 Rac-GTPase 信号传导 总的来说，我们的目标是开发具有生物活性的新型、有效、特异性的 Kalirin 抑制剂。 神经元。我们在突触生物学和 NPD 领域的专家之间建立了合作，高 通量筛选和计算药理学、药物化学和晶体学，以及 进行了广泛的初步研究，证明了我们的假设的有效性和可行性 我们的方法。我们提出以下具体目标：1）通过 HTS 进行命中发现，以识别小 分子与 kalirin 的 DHPH 结构域结合并抑制其 GEF 活性。 2) 蜂窝中的命中验证 和神经元测定。 3) 命中化合物作用机制的表征。 4) 药用 新型 GEF 抑制剂的化学优化