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

摘要 SARS-CoV-2与生物体的接触始于与其关键受体ACE 2的结合，ACE 2是一种高度 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， 病毒抑制呼吸道中纤毛的跳动，并抑制粘膜纤毛的运输，这是呼吸道疾病的第一道防线。 防御入侵的微生物。因此，增强纤毛功能可以防止病毒感染。 感染的最初步骤或帮助对抗病毒的进一步传播。ACE 2也表达为 在选定的脑细胞，潜在的SARS-CoV-2的神经影响。 这一补充的主要目标是迅速建立一个筛选系统，以确定药物， 立即应用于COVID-19治疗，并利用所获得的知识扩大 筛选出更广泛的候选化合物。 在我们的NIA支持的基金中，我们发现了nNOS-NO-CGC-cGMP信号传导的关键作用， 在大脑和呼吸道中纤毛活动的通路。在这里，我们描述了我们的计划， 与临床批准的药物一起使用，以增强纤毛活动和气道清除。这 该项目以后可以扩展到建立一个敏感和强大的抗COVID-19治疗药物筛选。 在我们的第一个具体目标，我们将开发一个全面的计算工具箱，并使用它来 确定呼吸道和大脑纤毛细胞中纤毛活动的关键参数（特征） 人和人源化小鼠模型。在第二个具体目标中，我们将把我们的设置应用于 确定纤毛对S1（SARS-CoV-2的主要细胞结合配体）的反应特征， 表达S1的假型VSV-S1病毒。最后，在我们的第三个具体目标，我们将审查反- 目前用于临床的SARS-CoV-2药物和临床批准的激活NO- cGMP途径，以及它们的组合，以确定这些治疗是否可以挽救S1受影响的 呼吸道和大脑准备中的纤毛活动。在同一组实验中，我们将检查 来自不同年龄动物的制剂的反应，这可能导致深度老龄化- COVID-19的偏见。我们强调，我们选择的药物进行测试是有限的， 治疗批准的化合物，从而使我们的研究结果迅速转化为临床 实践

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.