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Beta-cell responses to oxidative stress and Type 1 diabetes

β 细胞对氧化应激和 1 型糖尿病的反应

基本信息

批准号：
10406857
负责人：
Chad S Hunter
金额：
$ 63.51万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406857
关键词：
Ablation Address Aftercare Antioxidants Antiviral Response Attenuated Autoimmune Diseases Autoimmunity B-Lymphocytes Beta Cell Cell Maintenance Cell physiology Cells Characteristics Chronic Data Diabetes Mellitus Drug Modelings Etiology Exhibits Functional disorder Future Gene Expression Gene Expression Profile Generations Genes Genetic Human Immune In Vitro Inbred NOD Mice Inflammatory Response Insulin Insulin-Dependent Diabetes Mellitus Interferon Type I Leukocytes Link Manganese Mediating Messenger RNA Metalloporphyrins Modeling Mus NADPH Oxidase Non obese Onset of illness Oxidative Stress Participant Pharmaceutical Preparations Pharmacology Phenotype Proteins Reactive Oxygen Species Research Resistance Role Structure of beta Cell of islet Superoxides Testing Therapeutic Tissues blood glucose regulation chemokine comparative cytokine diabetes pathogenesis diabetic effector T cell experimental study in vivo inflammatory milieu insight insulin secretion islet mouse model preservation protein biomarkers response

项目摘要

Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β-cell destruction due to the generation of reactive oxygen species (ROS), proinflammatory cytokines/chemokines, and T cell effector molecules. Recent evidence has shown that β-cell dysfunction is also an activate participant in T1D pathogenesis. We will compare pancreatic β-cell functional identity changes that occur with T1D-prone Non-obese Diabetic (NOD) mice with T1D-resistant NOD.Ncf1m1J mice unable to generate NADPH oxidase (NOX)-derived superoxide. We will examine how the absence of ROS in NOD.Ncf1m1J mice can regulate β-cell functional identity, interactions with immune cells, and delay in T1D. To corroborate our genetic mouse models, we will examine pancreatic β-cell responses following treatment with a pharmacological manganese metalloporphyrin antioxidant with human islets. Our overarching hypothesis is that ROS reduction will preserve or enhance β-cell functional identity, as defined by transcriptional signatures and insulin secretion in T1D-prone NOD mice and human islets. To address this hypothesis, the following independent and interrelated aims will be defined: (1) Define how genetic ablation of ROS preserves β-cell functional identity. (2) Determine whether the absence of ROS can decrease pancreatic β-cell-mediated inflammatory responses. (3) Determine whether antioxidant treatment preserves the function of mouse and human β-cells. The insights gained from our studies will increase our understanding of diabetes etiology and may also point to future strategies employing antioxidant compounds to preserve and/or replace the function of pancreatic β-cells.

1型糖尿病（T1D）是一种自身免疫性疾病，由于产生活性氧（ROS）、促炎细胞因子/趋化因子和T细胞效应分子而导致胰腺β细胞破坏。最近的证据表明β细胞功能障碍也是T1D发病的激活参与者。我们将比较t1d易感非肥胖糖尿病（NOD）小鼠与t1d耐药NOD小鼠胰腺β细胞功能特性的变化。Ncf1m1J小鼠不能产生NADPH氧化酶（NOX）衍生的超氧化物。我们将研究NOD中ROS的缺失。Ncf1m1J小鼠可以调节β细胞的功能识别、与免疫细胞的相互作用和延迟T1D。为了证实我们的遗传小鼠模型，我们将在人类胰岛上使用锰金属卟啉抗氧化剂治疗后检测胰腺β细胞的反应。我们的主要假设是，ROS减少将保留或增强β细胞的功能特性，这是由t1d易发NOD小鼠和人类胰岛的转录特征和胰岛素分泌所定义的。为了解决这一假设，将定义以下独立且相互关联的目标：(1)定义ROS的基因消融如何保持β细胞的功能特性。(2)判断ROS缺失是否能降低胰腺β细胞介导的炎症反应。(3)确定抗氧化处理是否保留小鼠和人β细胞的功能。从我们的研究中获得的见解将增加我们对糖尿病病因的理解，也可能指出未来使用抗氧化化合物来保护和/或取代胰腺β细胞功能的策略。