Nitric oxide-mediated changes in glymphatic and CSF systems in aging and Alzheimer's disease

一氧化氮介导的类淋巴和脑脊液系统在衰老和阿尔茨海默病中的变化

• 批准号: 10177549
• 负责人: Helene D Benveniste
• 金额: $ 46.35万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177549
• 关键词: 2019-nCoV; Administrative Supplement; Affect; Age; Aging; Alzheimer' s Disease; Animals; Award; Bacteria; Binding; Binding Proteins; Brain; Brain Injuries; COVID-19; Cells; Cerebral Ventricles; Cerebrospinal Fluid; Cilia; Clinic; Clinical; Cyclic GMP; Drug Screening; Drug usage; Epithelial; Epithelium; Funding; Goals; Grant; Human; Infection; Invaded; Knowledge; Ligand Binding; Ligands; Mediating; Methods; Mucociliary Clearance; Mucous body substance; Nervous system structure; Neurologic Effect; Nitric Oxide; Nose; Organism; Pathway interactions; Pharmaceutical Preparations; Physiological; Preparation; Preventive measure; Preventive therapy; Process; Role; Signal Pathway; System; Techniques; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Trachea; Translations; United States National Institutes of Health; Vesicular stomatitis Indiana virus; Viral; Virus; Virus Diseases; aging brain; airway epithelium; analog; brain cell; clinical practice; drug candidate; drug testing; experimental study; fighting; glymphatic system; humanized mouse; improved; microorganism; mouse model; prevent; programs; receptor; receptor binding; response; screening; therapeutic candidate

ABSTRACT SARS-CoV-2 contact with the organism starts with binding to its key receptor ACE2 which is highly expressed in the ciliated cells of the tracheal, bronchial, and nasal mucociliary epithelium. After binding, the virus inhibits the cilia beating in the airways and suppresses mucociliary transport, the first line of defense against invading microorganisms. Thus, augmenting the ciliary function may prevent the viral infection at the very first steps or help fight the further propagation of the virus. ACE2 is also expressed in selected brain cells, underlying the neurological effects of SARS-CoV-2. The main objective of this supplement is to rapidly build a screening system, to identify drugs that can be immediately applied for COVID-19 therapy, and to use the gained knowledge for expanding the screen to a broader range of candidate compounds. In our NIA supported grant we discovered the critical role of the nNOS-NO-cGC-cGMP signaling pathway for ciliary activity in the brain and the airways. Here we describe our plans of targeting this pathway with clinically-approved drugs in order to augment cilia activity and airways clearance. This project can be later extended to build a sensitive and powerful drug screen for anti-COVID-19 therapy. In our first Specific Aim we will develop a comprehensive computational toolbox and use it to determine the key parameters (a signature) of the cilia activity in the airways’ and brain ciliated cells from humans and humanized mouse model. In the second Specific Aim, we will apply our setup to determine the signature of the cilia response to S1, the main cell binding ligand of SARS-CoV-2, and to S1-expressing pseudotyped VSV-S1 virus. Finally, in our third Specific Aim we will examine anti- SARS-CoV-2 drugs currently used in clinic and clinically-approved compounds that activate the NO- cGMP pathway, as well as their combination to determine if such treatments can rescue the S1-affected cilia activity in the airways and brain preparations. In the same set of experiments we will examine the response of preparations from animals of different age, which may contribute to the profound old age- bias of COVID-19. We emphasize that our selection of drugs to be tested is limited to the therapeutically-approved compounds, thus enabling rapid translation of our findings into clinical practice.

抽象的 SARS-CoV-2 与生物体的接触始于与其关键受体 ACE2 的结合，该受体高度 在气管、支气管和鼻粘膜纤毛上皮的纤毛细胞中表达。绑定后， 该病毒抑制气道中的纤毛跳动并抑制粘膜纤毛运输，这是呼吸道的第一道防线。 防御微生物的入侵。因此，增强纤毛功能可以预防病毒感染。 在最初的步骤中感染或帮助阻止病毒的进一步传播。 ACE2也表达 在选定的脑细胞中，SARS-CoV-2 的神经系统效应是潜在的。 该补充的主要目的是快速建立一个筛选系统，以确定可以 立即应用于 COVID-19 治疗，并利用所获得的知识来扩大 筛选更广泛的候选化合物。 在 NIA 支持的资助中，我们发现了 nNOS-NO-cGC-cGMP 信号传导的关键作用 大脑和气道中纤毛活动的通路。在这里，我们描述了我们针对此目标的计划 途径与临床批准的药物，以增强纤毛活动和气道清除。这 该项目稍后可以扩展，为抗 COVID-19 治疗建立灵敏且强大的药物筛选。 在我们的第一个具体目标中，我们将开发一个全面的计算工具箱并用它来 确定气道和大脑纤毛细胞中纤毛活动的关键参数（特征） 来自人类和人源化小鼠模型。在第二个具体目标中，我们将应用我们的设置 确定纤毛对 S1（SARS-CoV-2 的主要细胞结合配体）反应的特征，并 表达 S1 的假型 VSV-S1 病毒。最后，在我们的第三个具体目标中，我们将研究反 目前临床上使用的SARS-CoV-2药物和临床批准的激活NO-的化合物 cGMP 途径，以及它们的组合，以确定此类治疗是否可以拯救 S1 受影响的患者 气道中的纤毛活动和大脑准备。在同一组实验中，我们将检查 不同年龄动物的制剂反应，这可能导致深刻的老年- COVID-19 的偏见。我们强调，我们选择的待测药物仅限于 治疗上批准的化合物，从而使我们的发现能够快速转化为临床 实践。