The Role of Oxidative Phosphorylation Complexes in Beta Cell Biology

氧化磷酸化复合物在 β 细胞生物学中的作用

基本信息

批准号：
10612786
负责人：
Anna L Lang
金额：
$ 7.38万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
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：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10612786
关键词：
Affect Animals Antioxidants Area Beta Cell Biological Markers Biosensor Calcium Cardiomyopathies Cell Death Cell Energetics Cell membrane Cell physiology Cellular biology Chronic Collaborations Complex Coupling Critical Thinking Cytosol Data Defect Development Diabetes Mellitus Disease Electron Transport Complex III Environment Exocytosis Experimental Designs Functional disorder Glucose Goals Human Hyperglycemia Individual Inflammation Inherited Inner mitochondrial membrane Insulin Knock-out Knowledge Laboratories Learning LoxP-flanked allele Mediating Mentors Metabolic Metabolism Mitochondria Mitochondrial Diseases Modeling Morphology Mus Nerve Degeneration Neurons Oxidative Phosphorylation Oxidative Phosphorylation Deficiency Oxidative Stress Pancreas Pathogenicity Pathologic Pathology Pathway interactions Patients Phenotype Physiology Process Production Reactive Oxygen Species Research Respiration Role Sampling Signal Pathway Stimulus Structure of beta Cell of islet System Technical Expertise Testing Training Translating Work blood glucose regulation cell type complex IV diabetes pathogenesis diabetic endoplasmic reticulum stress glucose production human disease in vivo insight insulin granule insulin secretion insulin signaling islet mitochondrial dysfunction mitochondrial metabolism mouse model novel protein complex protein expression response

项目摘要

Project Summary The insulin-secreting pancreatic beta cell is a highly metabolic cell type and its dysfunction is a main cause of diabetes pathogenesis. The beta cell is reliant on mitochondrial function and energy production for glucose- stimulated insulin secretion. Mitochondrial ATP production is accomplished by 5 multi-subunit complexes of the oxidative phosphorylation (OXPHOS) system. The increase in the ATP:ADP ratio in the beta cell cytosol is the triggering signal for insulin release. Although a net decrease in ATP production would have an impact on beta cell function and insulin secretion, the impact of individual OXPHOS complex defects on beta cell biology and function remains unknown. Indeed, there are a broad spectrum of human diseases caused by defects in individual OXPHOS complexes ranging from neurodegeneration to cardiomyopathies, including maternally- inherited diabetes, suggesting a diverse range of downstream pathomechanisms. Therefore, the objective of this proposal is to elucidate the impact of three individual OXPHOS complexes (Complex I, III, and IV) in the context of the pancreatic beta cell. The hypothesis is that defects in individual OXPHOS complexes will result in distinct signaling pathway changes that will alter beta cell biology. Based on preliminary data, it is also hypothesized that Complex III deficient islets develop a severe hyperglycemic phenotype due to increased production of reactive oxygen species and oxidative stress. This proposal and training plan will provide the applicant with an excellent training environment with two recognized experts in islet physiology and mitochondrial diseases as co-mentors. Being a collaboration between two laboratories will allow the applicant ample opportunities to broaden her knowledge of a new research area, learn new scientific models and technical skills, enhance her critical thinking and rigorous experimental design, and set the stage to translate research questions to human pancreatic samples.

项目摘要分泌胰岛素胰腺β细胞是一种高度代谢细胞类型，其功能障碍是糖尿病发病机理。 β细胞依赖于葡萄糖的线粒体功能和能量产生刺激的胰岛素分泌。线粒体ATP的产生是通过5个多育种复合物完成的氧化磷酸化（OXPHOS）系统。 β细胞胞质中ATP：ADP比的增加是触发胰岛素释放的信号。尽管ATP生产的净减少将对Beta产生影响细胞功能和胰岛素分泌，单个Oxphos复合缺陷对β细胞生物学和功能仍然未知。确实，存在着许多由缺陷引起的广泛的人类疾病从神经退行性变化到心肌病，包括母亲 - 继承的糖尿病，表明下游病理机理各种。因此，这个目的建议是阐明在上下文中三个单独的Oxphos复合物（复合物I，III和IV）的影响胰腺β细胞。假设是单个Oxphos复合物中的缺陷将导致不同信号通路变化将改变β细胞生物学。基于初步数据，还假设复合物III缺乏胰岛由于反应性的产生增加而形成严重的高血糖表型氧和氧化应激。该建议和培训计划将为申请人提供出色的培训环境与两名公认的胰岛生理学专家和线粒体疾病作为联合疾病。作为两个实验室之间的合作，将使申请人有足够的机会扩大她了解新的研究领域，学习新的科学模型和技术技能，增强她的批判性思维和严格的实验设计，并为将研究问题转化为人类胰腺样品。