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（CF）是美国第五大死亡原因。作为一种临生遗传疾病，CF是 由于全身注射，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）。与众不同 CFRD是常见的I型或II型糖尿病，在患有CF和CF和 导致肺部疾病严重恶化。虽然新疗法 - 例如三重组合CFTR 调节剂疗法Trikafta - 对许多患者影响肺功能，这些疗法似乎没有 解决CF患者遇到的内分泌问题。早期的更精确和有效的方法 迫切需要检测该疾病以预防进展并大大降低死亡率。 如果成功的话，该项目将把CFRD患者的管理转变为更有效的治疗 策略。我们的第一个目标是了解MT1E在β细胞功能和生存过程中的作用 CFRD的发展。我们的第二个目标是阐明表达突变体CFTR的外分泌细胞的影响 在内分泌小岛上。我们的第三个目标是从健康，CFRD，CFRD，CFRD的胰岛单细胞（SCRNA-SEQ）地图。 和Trikafta处理的CF雪貂。我们的中心假设是氧化还原不平衡和组织重塑 通过通过金属硫氨酸1 E途径改变内分泌功能来促进CFRD进展。第一的， 预计该项目在调节中阐明了金属氨酸1e（MT1E）的分子机制 使用多能干细胞衍生的人胰腺外分泌和 内分泌器官。第二，通过使用尖端的胶原蛋白磁共振成像，该项目 将在CFRD开发过程中绘制胰腺纤维化的位置和严重程度。最后，表演 CFRD前临床模型的高吞吐量单细胞RNA测序分析，CFTRG551D/-KI雪貂， 该项目将确定CFRD进展过程中必不可少的生物标志物。最终，这些研究扩大了 我们对CFRD发病机理的理解，并为使用磁共振成像提供了基础 （MRI）作为疾病早期检测的潜在诊断方法。该项目也是机会 PI在其研究计划中转移方向，学习新技术将极大地促进他的未来 职业。