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Novel Drug Discovery for AD Targeting Ryanodine Calcium Channels

针对 Ryanodine 钙通道的 AD 新药发现

基本信息

批准号：
9028443
负责人：
John K Buolamwini
金额：
$ 195万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9028443
关键词：
APP-PS1 Acute Affect Agonist Alzheimer&apos s Disease Amyloid Amyloid deposition Back Behavioral Assay Biochemical Biological Biological Assay Biological Preservation Blood - brain barrier anatomy Calcium Calcium Channel Calcium Signaling Cell Culture System Cell Line Cell model Cells Cellular Assay Chronic Clinical Trials Cognitive deficits Dantrolene Data Dementia Dendritic Spines Development Disease Progression Electron Microscopy Electrophysiology (science)Endoplasmic Reticulum Functional disorder Furans Future Generations Hippocampus (Brain)Histopathology Homeostasis Human Image Immunoassay Impaired cognition Lead Link Measures Mediating Membrane Memory Memory Loss Mus Neurons Pathogenesis Pathology Pathway interactions Patients Performance Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Physiological Preparation Procedures Process Property Protein Isoforms Public Health Regimen Risk Risk Factors RyR1 RyR2 RyR3 Ryanodine Ryanodine Receptor Calcium Release Channel Series Signal Transduction Slice Solubility Specificity Staging Structure Synapses Synaptic Transmission Synaptic plasticity Testing Therapeutic Therapeutic Effect Treatment Protocols analog base carvedilol cognitive ability cognitive function design disorder control drug development drug discovery effective therapy improved in vitro activity in vivo iterative design mouse model neuron loss neurotransmission novel novel therapeutics patch clamp pharmacophore pre-clinical prevent public health relevance research clinical testing response scaffold screening small molecule synaptic function tau Proteins therapy outcome two-photon

项目摘要

DESCRIPTION (provided by applicant): Currently, there are no effective strategies or treatments to preserve cognitive function in AD patients. The recent series of disappointing clinical trials highlight the need to explore alternative pathways. Novel compounds that can preserve cognitive function and prevent disease progression in a manner distinct from previous approaches could provide new therapeutic opportunities. To this end, we are developing and testing small molecule compounds designed as allosteric modulators of the ryanodine receptor (RyR), a large conductance calcium channel found on the ER membrane, as candidates for clinical testing in early AD or MCI patients. In both human AD patients and AD mouse models, increased RyR2 expression precedes the amyloid deposition, tau histopathology, neuronal loss, and cognitive impairments. In AD mouse models, increased RyR-evoked calcium release is greatest in dendritic spines and synaptic compartments, and contributes to synaptic pathology and dysfunction, increased amyloid and tau pathology, disrupted memory function, and other AD-defining features. We and others have recently demonstrated that treating AD mice with dantrolene, a RyR channel stabilizer, resulted in exciting therapeutic effects. Although our treatment regimens differed, the consistent results demonstrate normalized calcium signaling (Chakroborty et al., 2012a; Oule et al., 2012; Stutzmann et al., 2006), normal synaptic transmission and plasticity expression (Chakroborty et al., 2012a), restored synaptic structure and integrity (Briggs et al., 2014), reduced A levels (Chakroborty et al., 2012a; Oule et al., 2012; Peng et al., 2012), restored RyR isoform levels (Chakroborty et al., 2012a; Oule et al., 2012), and improved performance on memory tests (Oule et al., 2012; Peng et al., 2012; Stutzmann lab, unpublished data). These data support a strong case for stabilizing RyR function, with a focus on RyR2, as a novel therapeutic strategy for AD. The objective of this study is to design, test, and optimize compounds that will function as RyR channel negative allosteric modulators, serving to suppress excessive calcium release while maintaining physiological functions. The central hypothesis is that development and optimization of small molecule RyR stabilizers will generate therapeutic leads for clinical testing in early AD and MCI patients, and through the preservation of calcium homeostasis and synaptic function, will protect cognitive abilities. This will be accomplished with the following Aims: 1. Compound development and medicinal chemistry optimization. This will use iterative medicinal chemistry procedures and bioactivity assays in mice. 2. Rapid screening assay in cell culture systems and neurons from AD mice. Initial screening will use automated fluorometric testing of RyR-evoked calcium signals in cultured N2A cells in 96-well plates, followed by screening in primary neurons from control and AD mice. 3. In vivo verification in mouse models. Sub chronic treatment in AD and control mice, followed by physiological and biochemical assays, will then be used to identify and finalize the optimal compounds. The significance to public health is the availability of an effective and novel treatment for AD.

描述（由申请人提供）：目前，尚无有效的策略或治疗方法来保护 AD 患者的认知功能。最近一系列令人失望的临床试验凸显了探索替代途径的必要性。能够以与以前的方法不同的方式保留认知功能并预防疾病进展的新型化合物可以提供新的治疗机会。为此，我们正在开发和测试设计为兰尼碱受体 (RyR)（一种在内质网膜上发现的大电导钙通道）变构调节剂的小分子化合物，作为早期 AD 或 MCI 患者临床测试的候选药物。在人类 AD 患者和 AD 小鼠模型中，RyR2 表达增加先于淀粉样蛋白沉积、tau 组织病理学、神经元损失和认知障碍。在 AD 小鼠模型中，RyR 诱发的钙释放增加在树突棘和突触室中最为明显，并导致突触病理和功能障碍、淀粉样蛋白和 tau 蛋白病理增加、记忆功能破坏以及其他 AD 定义特征。我们和其他人最近证明，用丹曲林（一种 RyR 通道稳定剂）治疗 AD 小鼠可产生令人兴奋的治疗效果。尽管我们的治疗方案有所不同，但一致的结果表明钙信号传导正常化（Chakroborty et al., 2012a; Oule et al., 2012; Stutzmann et al., 2006），正常的突触传递和可塑性表达（Chakroborty et al., 2012a），恢复了突触结构和完整性（Briggs et al., 2014），降低了A水平（查克罗博蒂等人， 2012a；欧勒等人，2012； Peng 等人，2012），恢复了 RyR 同工型水平（Chakroborty 等人，2012a；Oule 等人，2012），并提高了记忆测试的性能（Oule 等人，2012；Peng 等人，2012；Stutzmann 实验室，未发表的数据）。这些数据支持稳定 RyR 功能（重点是 RyR2）作为 AD 的新型治疗策略。本研究的目的是设计、测试和优化充当 RyR 通道负变构调节剂的化合物，在维持生理功能的同时抑制过多的钙释放。核心假设是，小分子 RyR 稳定剂的开发和优化将为早期 AD 和 MCI 患者的临床测试产生治疗线索，并通过保持钙稳态和突触功能，保护认知能力。这将通过以下目标来实现： 1. 化合物开发和药物化学优化。这将使用迭代药物化学程序和小鼠生物活性测定。 2. AD小鼠细胞培养系统和神经元的快速筛选分析。初步筛选将使用自动荧光检测 96 孔板中培养的 N2A 细胞中 RyR 诱发的钙信号，然后筛选来自对照和 AD 小鼠的原代神经元。 3.小鼠模型体内验证。对 AD 和对照小鼠进行亚慢性治疗，然后进行生理和生化测定，然后将用于鉴定和最终确定最佳化合物。对公共健康的重要性在于提供一种有效且新颖的 AD 治疗方法。