Control of beta cell identity by the mitochondrial life cycle

通过线粒体生命周期控制 β 细胞身份

基本信息

批准号：
10454761
负责人：
Scott Soleimanpour
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454761
关键词：
Address Anabolism Antioxidants B-Cell Development Back Beta Cell Biogenesis Biosensor Blood Glucose Cell Survival Cells Characteristics Chromatin Chronic Disease DNA Data Defect Diabetes Mellitus Diabetes prevention Ensure Environment Equilibrium Etiology Exhibits Failure Feedback Future Gene Expression Gene Expression Profile Genes Genetic Glucose Goals Health Human Hyperglycemia Impairment Insulin Lead Life Cycle Stages Maintenance Mediating Metabolic Metabolism Mitochondria Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Pancreas Patients Peripheral Pharmacology Physiological Power Plants Quality Control Reporting Respiration Role Signal Pathway Signal Transduction Structure Structure of beta Cell of islet Techniques Testing Veterans biological adaptation to stress diabetes pathogenesis fatty acid metabolism genetic approach in vivo insight insulin secretion islet metabolomics mitochondrial dysfunction novel oxidative damage preservation programs response stem cells tool transcriptomics

项目摘要

Diabetes results from insufficient functional pancreatic β-cell mass to meet peripheral insulin demands. β-cell failure can occur in T2D due to loss of β-cell identity or de-differentiation, with recent studies suggesting that loss of the mitochondrial gene expression program heralds the immature β-cell state. β-cells rely upon mitochondrial respiration to generate the energy necessary for the metabolic demands of insulin biosynthesis, processing, and secretion. Indeed, defects in mitochondrial structure, function, and DNA levels have been reported in the β-cells of patients with type 2 diabetes (T2D). Defects in mitochondrial structure and function are characteristic of impairments in the mitochondrial life cycle, which maintains functional mitochondrial mass via a balance of biogenesis and turnover. It is not clear, however, if impaired mitochondria are necessary and sufficient to directly induce β-cell immaturity. Interestingly, our preliminary data suggest that genetic loss of biogenesis or mitophagy reduces β-cell maturity and mass, which is not due to impaired β-cell replication or survival. Therefore, our goal is to dissect the mechanistic contribution of mitochondrial biogenesis and turnover to β-cell maturity and elucidate their contribution to diabetes pathogenesis. The central hypothesis to be tested is that defects in the mitochondrial life cycle induce a retrograde signaling cascade that impairs β-cell identity. We will test this hypothesis by the following approach: Specific Aim 1 will elucidate the effect of metabolic overload on the mitochondrial life cycle and its control of β-cell identity. Specific Aim 2 will determine the contribution of mitochondria derived oxidative damage to the development of β-cell immaturity. Specific Aim 3 will delineate the role of the integrated stress response to consolidate retrograde signals inducing β-cell immaturity following mitochondrial dysfunction. We anticipate obtaining a clear understanding of the importance and translational relevance of the mitochondrial life cycle by revealing the key effectors that mediate mito-nuclear crosstalk and impact β-cell identity. These results should re-define the role of mitochondria in diabetes pathogenesis and could open new possibilities to re-program immature β-cells back to a mature state to treat diabetes in Veterans.

糖尿病是由于功能性胰腺 β 细胞量不足以满足外周胰岛素需求而引起的。由于 β 细胞身份丧失或去分化，T2D 患者可能会出现失败，最近的研究表明，β 细胞丧失线粒体基因表达程序的异常预示着β细胞的不成熟状态依赖于线粒体。呼吸作用产生胰岛素生物合成、加工和代谢所需的能量事实上，β 细胞的线粒体结构、功能和 DNA 水平存在缺陷。 2 型糖尿病 (T2D) 患者的线粒体结构和功能缺陷是其特征。线粒体生命周期受损，通过平衡维持功能性线粒体质量然而，尚不清楚线粒体受损是否是直接影响的必要和充分条件。隐含地诱导β细胞不成熟，我们的初步数据表明生物发生或线粒体自噬的遗传损失。降低 β 细胞成熟度和质量，这不是由于 β 细胞复制或存活受损所致，因此，这是我们的目标。旨在剖析线粒体生物发生和周转对 β 细胞成熟的机制贡献并阐明它们对糖尿病发病机制的贡献待检验的中心假设是缺陷。线粒体生命周期会诱导逆行信号级联反应，从而损害 β 细胞身份。通过以下方法进行假设：具体目标 1 将阐明代谢超负荷对线粒体生命周期及其对 β 细胞身份的控制将决定具体目标 2 的贡献。线粒体衍生的氧化损伤会导致 β 细胞不成熟。具体目标 3 将描述。整合应激反应在巩固逆行信号中诱导β细胞不成熟的作用我们期望对线粒体功能障碍的重要性和转化有一个清晰的认识。通过揭示介导线粒体核串扰的关键效应器来研究线粒体生命周期的相关性这些结果应该重新定义线粒体在糖尿病发病机制中的作用，并可能。开辟新的可能性，将未成熟的β细胞重新编程回成熟状态，以治疗退伍军人的糖尿病。