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

在兔囊性纤维化模型中靶向 SGLT 治疗肝病

• 批准号: 10731085
• 负责人: JIE XU
• 金额: $ 65.97万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731085
• 关键词: Address; Adverse effects; Animal Model; Animals; Attenuated; Base Pairing; Bile Acids; Bile fluid; Biological Models; Blood Chemical Analysis; Cells; Clinical; Code; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Diabetes Mellitus; Disease; Epithelial Cells; Exclusion; Follow-Up Studies; Genetic Diseases; Glucose; Goals; Hepatocyte; Human; Impairment; Individual; Inflammation; Knowledge; Lipids; Liver; Liver Fibrosis; Liver diseases; Longevity; Lung; Medical; Metabolic Diseases; Modeling; Molecular; Mutation; Organoids; Oryctolagus cuniculus; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Preclinical Testing; RNA Splicing; Regulator Genes; Reporting; Research Priority; Safety; Sodium; Testing; Therapeutic Effect; Tissues; Transducers; United States Food and Drug Administration; Up-Regulation; Weight Gain; Work; XBP1 gene; airway epithelium; autosome; biological adaptation to stress; blood glucose regulation; cholangiocyte; cystic fibrosis patients; disease phenotype; disease-causing mutation; drug development; drug testing; efficacy testing; endoplasmic reticulum stress; experimental study; improved; inhibitor; inhibitor therapy; liver cystic fibrosis; liver function; mortality; nonalcoholic steatohepatitis; pharmacologic; pre-clinical; pulmonary function; symporter

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.

项目摘要 囊性纤维化（CF）相关肝病（CFLD）是CF的第三大死亡原因，CF是一种常染色体遗传性肝病。 囊性纤维化跨膜传导调节因子（CFTR）突变引起的遗传性疾病 基因约有20%~ 40%的CF患者患有CFLD，并且这一数字在过去呈上升趋势 十年令人担忧的是，最近批准的Trikafta，虽然显着改善肺功能， CF患者中的肝脏相关疾病，得到新临床报告的支持。治疗/治愈CFLD 后三国自由贸易协定时代现在成为最优先的研究课题。缺乏适当的临床前动物模型 对于CFLD一直是药物开发的限制因素。最近，我们生产了CF兔， 表明它们表现出许多典型的CF表型。重要的是，肝脏表型包括 观察到胆汁分泌异常、NASH样表型以及脂质和葡萄糖稳态受损， 将其作为CFLD和药物测试的有前途的模型。此外，我们还获得了强有力的初步结果。 有证据表明，钠依赖性葡萄糖协同转运蛋白（SGLT）抑制剂（SGLTi）治疗 对CF兔的CFLD表型具有令人惊讶的治疗效果。基于这些，我们假设“CFTR 突变->炎症& ER应激-> SGLT 1上调->代谢紊乱-> CFLD”形成恶性 循环，并且通过SGLTi药物破坏该循环对CFLD有益。为了验证这个假设，我们将 利用我们最近开发的携带显性患者突变CFTR-F508 del（dF）的CF兔， 两个具体目标：在目标1中，我们将确定Trikafta对dF兔肝脏的作用， 然后进行实验以确定SGLTi药物，如Sotaglivatinib和恩格列净，是否会带来任何 在Trikafta之上对DF兔肝的益处。在目标2中，我们将研究分子机制， SGLT抑制通过确定SGLTi药物对ER应激的影响而有益于CF肝病， 在dF兔肝脏和人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制证据。 成功的药物，即，SGLT抑制剂药物，用于未满足的医学挑战：后Trikafta时代的CFLD。