The Role of Oxidative Phosphorylation Complexes in Beta Cell Biology

项目摘要 分泌胰岛素的胰岛β细胞是一种高度代谢的细胞类型，其功能障碍是导致 糖尿病发病机制。β细胞依赖于线粒体的功能和葡萄糖的能量产生- 刺激胰岛素分泌。线粒体ATP的产生是由5个多亚单位复合体完成的 氧化磷酸化(OXPHOS)系统。β细胞胞浆中ATP/ADP比率的增加是 触发胰岛素释放信号。尽管ATP产量的净减少将对Beta产生影响 细胞功能和胰岛素分泌，个体OXPHOS复合体缺陷对β细胞生物学和 功能仍不清楚。事实上，有很多人类疾病都是由基因缺陷引起的。 单个OXPHOS复合体，从神经变性到心肌病，包括母体- 遗传性糖尿病，提示一系列下游的病理机制。因此，这样做的目的是 建议澄清三个单独的氧磷络合物(络合物I、III和IV)在上下文中的影响 胰岛β细胞。假设是单个OXPHOS复合体的缺陷将导致不同的 信号通路的改变将改变β细胞生物学。根据初步数据，还假设 复合体III缺乏的胰岛由于反应性分泌增加而发展为严重的高血糖表型 氧物种和氧化应激。此建议书和培训计划将为申请者提供优秀的 培训环境由两位公认的胰岛生理学和线粒体疾病专家共同指导。 作为两个实验室之间的合作，申请者将有足够的机会拓宽自己的领域 了解一个新的研究领域，学习新的科学模型和技术技能，增强她的批判性思维 和严谨的实验设计，并为将研究问题转化为人类胰腺奠定了基础 样本。

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.