Role of Metallothionein 1 E in the protection of cystic fibrosis-related diabetes

金属硫蛋白 1 E 在保护囊性纤维化相关糖尿病中的作用

• 批准号: 10714873
• 负责人: Xiangming Ji
• 金额: $ 38.26万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714873
• 关键词: Adipocytes; Adult; Age; Alpha Cell; Animal Model; Bacterial Infections; Beta Cell; Biological Markers; Caucasians; Cause of Death; Cell Death; Cell Line; Cell Survival; Cell physiology; Cells; Childhood; Collagen; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; D Cells; Death Rate; Delta F508 mutation; Development; Diabetes Mellitus; Disease; Early Diagnosis; Endocrine; Exhibits; Exocrine pancreas; FDA approved; Ferrets; Fibrosis; Functional disorder; Future; Gene Expression; Genes; Genetic Diseases; Genetic Transcription; Glucagon; Goals; Homeostasis; Human; Imaging Techniques; In Vitro; Infiltration; Inflammation; Insulin; Islet Cell; Islets of Langerhans; Knockout Mice; Knowledge; Lead; Learning; Life; Location; Lung; Lung diseases; Magnetic Resonance Imaging; Maps; Metallothionein; Methods; Modeling; Molecular; Molecular Genetics; Monitor; Morbidity - disease rate; Mucous body substance; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obstructive Lung Diseases; Organoids; Oxidation-Reduction; Pancreas; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Pluripotent Stem Cells; Pre-Clinical Model; Prevention; Production; Recovery; Research; Resolution; Role; Route; Severities; Signal Transduction; Somatostatin; Streptozocin; Structure of beta Cell of islet; Techniques; Testing; Time; Tissues; VX-770; Zinc; career; comorbidity; cystic fibrosis patients; cystic fibrosis related diabetes; diabetic; diagnostic strategy; effective therapy; endoplasmic reticulum stress; epithelial Na+ channel; experience; gastrointestinal system; human pluripotent stem cell; humanized mouse; imaging approach; impaired glucose tolerance; in vitro testing; in vivo; in vivo evaluation; islet; member; mouse model; mutant; novel; novel therapeutics; overexpression; programs; pulmonary function; single-cell RNA sequencing; systemic inflammatory response; treatment strategy

PROJECT SUMMARY/ABSTRACT Cystic fibrosis (CF) is the fifth leading cause of death in the US. As a life-shortening genetic disease, CF is characterized by abnormalities in the pulmonary and digestive systems due to systemic inflammation, fibrosis, and tissue degradation. About half of adult CF patients experience cystic fibrosis related diabetes (CFRD). Unlike the common type I or type II diabetes, CFRD develops at the very early stages of life of people with CF and leads to greatly worsened lung disease. Although new therapeutics – such as the triple combination CFTR modulator therapy TRIKAFTA – are impacting lung function for many patients, these therapies do not appear to be solving the endocrine problems experienced by people with CF. More precise and effective methods of early detection of this disease are urgently needed for progression prevention and to drastically lower the death rate. This project, if successful, will transform the management of patients with CFRD into more effective treatment strategies. Our first goal is to understand the role of MT1E on β-cell functions and survival during the development of CFRD. Our second goal is to elucidate the impact of exocrine cells expressing mutant CFTR on endocrine islets. Our third goal is to resolve a single-cell (scRNA-seq) map of islets from healthy, CFRD, and TRIKAFTA-treated CF ferrets. Our central hypothesis is that redox imbalance and tissue remodeling contribute to CFRD progression by altering endocrine function through the metallothionein 1 E pathway. First, this project is expected to shed light on the molecular mechanism of Metallothionein 1E (MT1E) in regulating pancreatic damage in patients with CFRD, using pluripotent stem cell-derived human pancreatic exocrine and endocrine organoids. Second, by using cutting-edge collagen-based magnetic resonance imaging, this project will map the location and severity of fibrosis in the pancreas during the development of CFRD. Finally, performing high throughput single-cell RNA sequencing analysis of the pre-clinical model of CFRD, the CFTRG551D/-KI ferret, this project will identify essential biomarkers during the progression of CFRD. Ultimately, these studies broaden our understanding of the pathogenesis of CFRD and provide the basis for using Magnetic resonance imaging (MRI) as a potential diagnostic approach for disease early detection. The project also serves as an opportunity for the PI to shift directions in his research program, learning new techniques that will greatly enable his future career.

项目总结/摘要 囊性纤维化（CF）是美国第五大死亡原因。作为一种缩短寿命的遗传性疾病，CF是 其特征在于由于全身炎症，纤维化， 和组织降解。大约一半的成年CF患者患有囊性纤维化相关糖尿病（CFRD）。不像 常见的I型或II型糖尿病，CFRD在CF患者生命的早期阶段发展， 导致肺部疾病严重恶化。虽然新的疗法-如三联CFTR 调节剂治疗TRIKAFTA -影响许多患者的肺功能，这些治疗似乎并不 解决CF患者的内分泌问题。更精确和有效的方法， 迫切需要检测这种疾病，以预防疾病进展并大幅降低死亡率。 如果该项目成功，将使对面板堆石坝患者的管理转变为更有效的治疗 战略布局我们的第一个目标是了解MT 1 E对β细胞功能和存活的作用， 开发CFRD。我们的第二个目标是阐明表达突变CFTR的外分泌细胞的影响 对内分泌胰岛的影响我们的第三个目标是解析来自健康、CFRD、 和TRIKAFTA治疗的CF雪貂。我们的中心假设是氧化还原失衡和组织重塑 通过金属硫蛋白1 E途径改变内分泌功能，促进CFRD进展。第一、 本项目有望阐明金属硫蛋白1 E（MT 1 E）在调节 使用多能干细胞衍生的人胰腺外分泌， 内分泌类器官其次，通过使用最先进的基于胶原蛋白的磁共振成像， 将绘制在面板堆石坝的发展过程中，胰腺纤维化的位置和严重程度。最后进行 CFRD临床前模型CFTRG 551 D/-KI雪貂的高通量单细胞RNA测序分析， 本项目将确定面板堆石坝施工过程中的重要生物标志物。最终，这些研究拓宽了 了解CFRD的发病机制，为磁共振成像的应用提供依据 (MRI)作为疾病早期检测的潜在诊断方法。该项目也是一个机会， 让PI在他的研究计划中改变方向，学习新技术，这将大大有助于他的未来 事业