Targeting SGLTs for liver disease in a rabbit model of cystic fibrosis

项目总结 囊性纤维化(CF)相关性肝病(CFLD)是导致常染色体囊性纤维化死亡的第三大原因 囊性纤维化跨膜传导调节因子突变引起的遗传病 吉恩。大约20%到40%的CFLD患者患有CFLD，而且这个数字在过去还在上升 十年。令人担忧的是，最近批准的Trikafta虽然显著改善了肺功能， 加重CF患者的肝脏相关疾病，得到了新的临床报告的支持。治疗/治疗CFLD 后Trikafta时代现在成为一个最优先的研究主题。缺乏合适的临床前动物模型 因为CFLD一直是药物开发的限制因素。最近，我们生产了CF兔和 证明了它们表现出许多典型的CF型。重要的是，肝脏表型包括 观察到异常的胆汁分泌，纳什样表型，以及脂糖平衡受损。 将它们作为CFLD和药物测试的一个有前途的模型。此外，我们还获得了很好的初步结果 钠依赖葡萄糖共转运体(SGLT)抑制剂(SGLTi)治疗作用的证据 对慢性阻塞性肺疾病兔CFLD表型的惊人疗效。在此基础上，我们假设“CFTR 突变-炎症与内质网应激--SGLT1上调--代谢紊乱-CFLD“形成恶性 SGLTi药物破坏这一循环对CFLD有利。为了检验这一假设，我们将 利用我们最近培育的携带显性患者突变CFTR-F508del(Df)的CF兔进行追踪 两个具体目标：在目标1中，我们将确定Trikafta的效果，重点是DF兔的肝脏， 然后进行实验，以确定SGLTI药物，如索他利弗津和恩帕利弗津，是否会带来 在Trikafta上对DF兔肝的好处。在目标2，我们将研究分子机制，通过它 SGLT抑制通过测定SGLTi药物对内质网应激和肝纤维化的影响而有益于慢性肝病 DF兔肝脏以及人DF胆管细胞和肝细胞中的炎症途径。我们的工作将 为扩大(或不扩大)这类特殊药物的使用提供临床前和机械证据 成功的药物，即SGLT抑制剂药物，以应对一个未得到满足的医学挑战：后Trikafta时代的CFLD。

PROJECT SUMMARY Cystic fibrosis (CF)-related liver disease (CFLD) is the third-leading cause of mortality in CF, an autosomal genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Approximately 20% to 40% CF patients suffer from CFLD, and the number is on the rise in the past decade. Of concern, the recently approved Trikafta, although significantly improves the pulmonary functions, worsens liver related disorders in CF patients, supported by emerging clinical reports. Treating/curing CFLD in the post-Trikafta era now becomes a top priority research topic. A lack of appropriate preclinical animal models for CFLD has been a limiting factor for drug development. Recently, we produced CF rabbits and demonstrated that they manifest many typical CF phenotypes. Importantly, liver phenotypes including abnormal bile secretion, NASH-like phenotypes, and impaired lipid and glucose homeostasis were observed, presenting them as a promising model for CFLD and drug testing. Further, we obtained strong preliminary evidence that treatments of sodium-dependent glucose cotransporter (SGLT) inhibitors (SGLTi) exerted surprising therapeutic effects on CFLD phenotypes of CF rabbits. Based on these, we hypothesize that “CFTR mutation -> inflammation & ER stress -> SGLT1 upregulation -> metabolic disorder -> CFLD” form a vicious circle and that disruption of this circle by SGLTi drugs is beneficial for CFLD. To test this hypothesis, we will utilize our recently developed CF rabbits carrying the dominant patient mutation CFTR-F508del (dF) to pursue two specific aims: in Aim 1, we will determine the effects of Trikafta with a focus on the livers of dF rabbits, followed by experiments to determine if SGLTi drugs, such as Sotagliflozin and Empagliflozin, bring any benefits to dF rabbit livers on top of Trikafta. In Aim 2, we will investigate the molecular mechanisms by which SGLT inhibition benefits CF liver disease by determining the effects of SGLTi drugs on the ER stress and inflammation pathways in dF rabbit livers and in human dF cholangiocytes and hepatocytes. Our work will provide preclinical and mechanistic evidence for expanding (or not) the use of this class of extraordinary successful drugs, i.e., SGLT inhibitor drugs, for an unmet medical challenging: CFLD in the post-Trikafta era.