Probing brain circuit and behavior with protein:protein interaction modulators

用蛋白质探测大脑回路和行为：蛋白质相互作用调节剂

• 批准号: 10607051
• 负责人: Fernanda Laezza
• 金额: $ 82.42万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607051
• 关键词: Action Potentials; Acute; Affect; Anhedonia; Behavior; Behavioral; Binding; Biological; Biological Assay; Biology; Bioluminescence; Brain; Brain Diseases; Cardiac; Cells; Central Nervous System Agents; Chemicals; Classification; Clinical; Collection; Communities; Complement; Complex; Development; Disease; Dose; Drug Design; Drug Kinetics; Electrophysiology (science); Excretory function; Fluorescence; Foundations; Functional disorder; Genetic; Globus Pallidus; Goals; Ion Channel; Knowledge; Lead; Ligand Binding; Ligands; Link; Luciferases; Manuals; Measures; Mental disorders; Metabolic; Metabolism; Molecular; Molecular Probes; Motivation; Mus; Nature; Nervous System; Neurons; Neuropharmacology; Nucleus Accumbens; Outcome; Output; Pathway interactions; Permeability; Process; Protein Isoforms; Proteins; Regulation; Research; Rewards; Role; SCN8A gene; Slice; Solubility; Surface Plasmon Resonance; Therapeutic; Toxic effect; Transgenic Mice; Validation; Ventral Tegmental Area; absorption; addiction; behavior test; blood-brain barrier permeabilization; cell type; clinical efficacy; design; drug discovery; fibroblast growth factor-14; flexibility; gamma-Aminobutyric Acid; hedonic; high throughput screening; improved; in vitro activity; in vivo; innovation; intermolecular interaction; loss of function; luminescence; motivated behavior; mutant; nanomolar; neural circuit; neuronal excitability; neuropsychiatric disorder; novel; novel therapeutic intervention; optogenetics; patch clamp; pre-clinical; protein protein interaction; psychologic; receptor; response; small molecule; small molecule libraries; therapeutic development; tool; validation studies; voltage

ABSTRACT Psychiatric diseases are complex brain disorders associated with maladaptive plasticity of the brain circuit for which we lack predictive preclinical measures of clinical efficacy. To fill this gap, we need to use molecular knowledge to inform development of novel probes in order to interrogate the mechanisms that underlie circuit deficits in these disorders and drive advanced therapeutic design. Protein-protein interactions (PPI) within ion channel complexes fine-tune neuronal excitability and are emerging as links to the biology of psychiatric disorders. Their highly specific and flexible interfaces make protein-channel interactions ideal targets for probe development. Such molecular probes would provide the neuropharmacology community with optimal research tools to parse out brain disease complexities and enable more effective drug design. We have identified the PPI between the voltage-gated Na+ (Nav) Nav1.6 channel and its accessory regulator protein, fibroblast growth factor 14 (FGF14) as a functionally relevant regulator of excitability of medium spiny neurons (MSN) in the nucleus accumbens (NAc); a central component of the mesocorticolimbic circuit whose dysfunction has been associated with a wide spectrum of neuropsychiatric disorders. Through a bioluminescence-based high-throughput screen (HTS) and a round of chemical optimization we have identified the new brain permeable probe 1028 that modulates FGF14:Nav1.6 channel complex formation and increases Nav1.6 channel availability and MSN firing. When systemically administrated, 1028 increases accumbal neuron firing and promotes hedonic states in situations lacking motivation, suggesting the compound can modulate reward-related behaviors within the mesocorticolimbic circuit. Here, we are proposing to further optimize 1028 for in vivo use by improving its potency and metabolic stability and determine its mechanism of action at the molecular (Aim 1), cellular (Aim 2), circuital, and behavioral levels (Aim 3). Outcomes of this proposed research will generate the first-in-class brain-permeant chemical probes to interrogate the reward circuit, providing the foundation for pre-therapeutic development of a new class of PPI-based leads for a broad spectrum of psychiatric disorders.

摘要 精神疾病是一种复杂的大脑疾病，与大脑回路的不适应可塑性有关 我们缺乏临床疗效的预见性临床前措施。为了填补这一空白，我们需要使用分子 为开发新的探头提供信息的知识，以便询问电路背后的机制 这些疾病的缺陷，并推动先进的治疗设计。离子内蛋白质-蛋白质相互作用(PPI) 通道复合体微调神经元的兴奋性，并正在成为精神病学生物学的纽带 精神错乱。它们高度特异和灵活的界面使蛋白质-通道相互作用成为理想的探针目标 发展。这样的分子探针将为神经药理学社区提供最佳研究 分析大脑疾病复杂性并实现更有效的药物设计的工具。 我们已经确定了电压门控Na+(Nav)Nav1.6通道与其辅助调节器之间的PPI 成纤维细胞生长因子14(FGF14)作为中棘兴奋性的功能相关调节因子 伏核(NAC)中的神经元(MSN)；中皮质边缘回路的中心成分，其 功能障碍与一系列神经精神障碍有关。通过一个 基于生物发光的高通量筛选(HTS)和我们已经确定的一轮化学优化 新的脑透性探针1028调节FGF14：Nav1.6通道复合体的形成并增加 Nav1.6频道可用性和MSN触发。当系统管理时，1028增加累积量 在缺乏动力的情况下，神经元激活并促进享乐状态，这表明该化合物可以 调节大脑中皮质边缘环路中的奖赏相关行为。在此，我们建议进一步 通过提高1028的效价和代谢稳定性来优化其体内使用，并确定其作用机制 在分子(目标1)、细胞(目标2)、回路和行为水平(目标3)采取行动。这样做的结果是 拟议中的研究将产生一流的大脑预想化学探测器来审问奖励 电路，为治疗前开发一类新的基于PPI的导线提供了基础 精神疾病的谱系。