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

基本信息

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
项目类别：
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

项目摘要

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死亡率的第三个主要原因，即常染色体由囊性纤维化跨膜电导调节剂（CFTR）突变引起的遗传疾病基因。大约20％至40％的CF患者患有CFLD，过去的数量在增加十年。令人担忧的是，最近批准的Trikafta虽然显着改善了肺功能，但在新兴临床报告的支持下，CF患者的肝脏相关疾病恶化。处理/治疗CFLD Trikafta后的擦除现在成为首要研究主题。缺乏适当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兔子和证明它们表现出许多典型的CF表型。重要的是，包括观察到异常的胆汁分泌，纳什样表型以及脂质和葡萄糖稳态受损，将它们作为CFLD和药物测试的有前途的模型。此外，我们获得了强大的初步依赖钠葡萄糖共转运蛋白（SGLT）抑制剂（SGLTI）的治疗的证据令人惊讶的对CF兔子CFLD表型的治疗作用。基于这些，我们假设“ CFTR 突变 - >炎症和ER压力 - > SGLT1上调 - >代谢障碍 - > CFLD” 圆圈和SGLTI药物对这个圆圈的破坏对CFLD有益。为了检验这一假设，我们将利用我们最近开发的CF兔子，携带主要的患者突变CFTR-F508DEL（DF）购买两个具体的目标：在AIM 1中，我们将确定Trikafta的影响，重点是DF兔子的生命，然后进行实验，以确定SGLTI药物（例如sotagliflozin和empagliflozin）是否带来任何对DF兔子的好处生活在Trikafta之上。在AIM 2中，我们将研究分子机制 SGLT抑制通过确定SGLTI药物对ER应激的影响和 DF兔子中的炎症途径生活，人类DF胆管细胞和肝细胞中的炎症途径。我们的工作将提供临床前和机械证据，以扩大（或不）使用此类非凡成功的药物，即SGLT抑制剂药物，以实现未满足的医学挑战：Trikafta后时代的CFLD。