Unraveling the role of the CFTR ion channel in susceptibility to SARS-CoV-2 infection and inflammation

总结 本行政补充（根据NIH PA-18-591现有NIH赠款的行政补充， 合作协议）寻求资金用于应对SARS-CoV-2/COVID-19爆发的研究， 福尔斯属于正在进行的赠款5 R 01 AI 124121 -05的范围。 最初的拨款（5 R 01 AI 124121 -05）专注于了解离子通道囊性纤维化的作用 跨膜电导调节剂（CFTR）对气道炎症加重的影响。患者 这种离子通道中的突变导致其功能障碍，发展为囊性纤维化（CF）， 受损的细菌清除和增加的肺部炎症，最终导致肺衰竭。作为离子 CFTR通过调节肺中的流体稳态来调节肺中的流体稳态。此外，我们发表的研究表明， 缺乏功能性CFTR的巨噬细胞第一次损害了自噬，导致过度的炎症反应。 profile.除了炎症之外，CFTR离子通道还在肺中的流体稳态中起作用，例如，在肺中，CFTR离子通道在肺中的流体稳态中起作用。 水肿。与本补充相关的是，我们小组的研究结果表明，CFTR降低的小鼠 （杂合子）严重急性呼吸综合征冠状病毒（SARS-CoV）的表达增加 和SARS-CoV-2受体ACE 2。新出现的病原体负责COVID-19，SARS-CoV-2，是一种 截至今天，全球威胁已造成全球42万多人死亡，预计将造成13万多人死亡。 到2020年6月底，仅在美国就有死亡人数。在目标1中，我们将鉴定出基因组中的突变和多态性。 CFTR基因在SARS-CoV-2阳性患者中的表达目标2将确定是否存在遗传关联 CFTR突变和多态性与呼吸系统疾病严重程度之间的关系。这项研究的结果将 揭示CFTR是否是COVID-19的修饰基因。这项研究将有助于识别患者倾向于 呼吸衰竭或死亡的SARS-CoV-2感染，并在他们死于呼吸衰竭之前进行管理。 失败未来的研究将建立增加CFTR功能的药理学化合物， COVID-19的治疗方法。

Summary This administrative supplement (under NIH PA-18-591 Administrative Supplements to Existing NIH Grants and Cooperative Agreements) seeks funding for research responsive to the SARS-CoV-2/COVID-19 outbreak that falls within the scope of the ongoing grant 5R01AI124121-05. The original grant (5R01AI124121-05) is focused on understanding the role of the ion channel Cystic Fibrosis Transmembrane conductance Regulator (CFTR) on exacerbated inflammation in the airways. Patients with mutations in this ion channel leading to its malfunction develop Cystic Fibrosis (CF), a disease associated with impaired bacterial clearance and increased lung inflammation, which ultimately results in lung failure. As an ion channel, CFTR regulates fluid homeostasis in the lung. In addition, our published studies demonstrated for the first time that macrophages lacking functional CFTR had impaired autophagy resulting in excessive inflammatory profile. In addition to inflammation, the CFTR ion channel plays also a role in fluid homeostasis in the lung such as edema. Relevant to this Supplement, findings from our group show that mice with reduced CFTR (heterozygous) have increased expression of the severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 receptor ACE2. The novel emergent pathogen responsible for COVID-19, SARS-CoV-2, is a global threat responsible for over 420,000 deaths worldwide as of today and is projected to cause >130,000 deaths in the US alone by the end of June 2020. In Aim 1, we will identify mutations and polymorphisms in the CFTR gene in SARS-CoV-2 positive patients. Aim 2 will determine whether there is a genetic association between CFTR mutations and polymorphisms and severity of respiratory disease. Findings from this study will reveal whether CFTR is a modifier gene to COVID-19. This study will help in the identification of patients prone to respiratory failure or death upon SARS-CoV-2 infection and manage them before they succumb to respiratory failure. Future studies will establish pharmacological compounds that increase CFTR function as new therapeutics for COVID-19.