Restoring macrophage function in cystic fibrosis

总结 本行政补充文件是对NOT-HL-19-724（特别利益通知（NOSI）：可用性）的回应 行政和修订补充，以扩大电子烟研究和理解EVALI）。).原始 格兰特（5 R 01 AI 124121 -04）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.与本补充文件相关的是，我们小组的研究结果显示， 和大麻中的精神活性成分δ-9-四氢大麻酚（THC）， CFTR导致“获得性CFTR功能障碍”。除了炎症，CFTR离子通道也起着重要作用。 在肺中的流体稳态中的作用，例如水肿。在过去的几个月里， 许多人在患上与电子烟有关的肺部疾病后死亡：“电子烟，或电子烟，产品使用相关 称为EVALI的“肺损伤”，其特征在于过度的肺部炎症和肺水肿。我们 因此，假设THC和/或维生素E醋酸酯抑制/降低CFTR功能将有助于 关于EVALI 在目标1中，我们将确定与以下相关的电子烟制剂中存在的不同试剂的效果： EVALI治疗肺部炎症。小鼠将暴露于雾化制剂，并对 将进行肺部炎症（多重，流式细胞术，RNAseq）。在目标2中，我们将确立 CFTR离子通道对EVALI样表型的影响。在这里，我们建议使用小鼠模型，表达不同的 CFTR水平（WT、Hets和KO）。CFTR活化剂也将进行测试，以评估其减少吸烟的能力。 诱发肺部炎症。

Summary This Administrative Supplement is in response to NOT-HL-19-724 (Notice of Special Interest (NOSI): Availability of Administrative and Revision Supplements to Expand Vaping Research and Understand EVALI). ). The original grant (5R01AI124121-04) 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. Relevant to this Supplement, findings from our group revealed that pollutants, such as cigarette smoke and the psychoactive ingredient present in marijuana delta-9-tetrahydrocannabinol (THC), negatively regulate CFTR leading to “acquired CFTR dysfunction”. In addition to inflammation, the CFTR ion channel plays also a role in fluid homeostasis in the lung such as edema. Within the past few months, several people were hospitalized and many died after developing lung disease linked to vaping: “e-cigarette, or vaping, product use-associated lung injury” called EVALI which is characterized by excessive lung inflammation and pulmonary edema. We therefore hypothesize that inhibition/decrease of CFTR function by THC and/or vitamin E acetate will contribute to EVALI. In Aim 1, we will determine the effect of the different agents present in vaping preparations associated with EVALI on lung inflammation. Mice will be exposed to vaping preparations and a comprehensive assessment of lung inflammation (multiplex, flow cytometry, RNAseq) will be performed. In Aim 2, we will establish the role of the CFTR ion channel on EVALI-like phenotype. Here we propose to use a mouse model that expresses different levels of CFTR (WT, Hets, and KO). CFTR activators will also be tested to evaluate their ability to reduce vaping- induced lung inflammation.