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.

项目摘要/摘要 囊性纤维化是美国第五大致死原因。作为一种缩短生命的遗传病，CF是 以肺部和消化系统异常为特征的，由全身炎症、纤维化、 和组织退化。大约一半的成人CF患者患有囊性纤维化相关性糖尿病(CFRD)。不像 CFRD是一种常见的I型或II型糖尿病，发生在CF患者生命的非常早期阶段 会导致肺部疾病的严重恶化。尽管新的疗法--如三联疗法-- 调节剂疗法TRIKAFTA-对许多患者的肺功能有影响，这些疗法似乎没有 正在解决CF患者所经历的内分泌问题。更准确、更有效的早期方法 迫切需要对这种疾病进行检测，以防止病情发展并大幅降低死亡率。 该项目如果成功，将把CFRD患者的管理转变为更有效的治疗 战略。我们的第一个目标是了解MT1E在β细胞功能和存活过程中的作用。 面板堆石坝的发展。我们的第二个目标是阐明外分泌细胞表达突变CFTR的影响 在内分泌岛上。我们的第三个目标是解析来自健康的、CFRD、 和经TRIKAFTA处理的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1E途径改变内分泌功能，参与CFRD的进展。第一, 本项目有望阐明金属硫蛋白1E(MT1E)调控的分子机制 使用多能干细胞来源的人胰腺外分泌物和联合应用于CFRD患者的胰腺损害 内分泌类器官。其次，通过使用尖端的胶原蛋白磁共振成像，该项目 将绘制出在CFRD发展过程中胰腺纤维化的位置和严重程度。最后，表演 CFTRG551D/-KI雪貂临床前模型的高通量单细胞RNA测序分析 该项目将确定CFRD进展过程中的基本生物标记物。最终，这些研究拓宽了 我们对CFRD发病机制的认识，为磁共振成像的应用提供了依据 (MRI)作为一种潜在的疾病早期发现的诊断方法。该项目也是一个机会 对于PI来说，改变他的研究计划的方向，学习新的技术，这将极大地使他的未来 职业生涯。