Nrf2 and the adaptive expansion of beta cell mass

Nrf2 和 β 细胞质量的适应性扩张

• 批准号: 9924265
• 负责人: DONALD K. SCOTT
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924265
• 关键词: Address; American; Antioxidants; Beta Cell; Binding Proteins; Biogenesis; Carbohydrates; Cell Death; Cell Proliferation; Cellular Metabolic Process; Cellular biology; Clinical Trials; Data; Diabetes Mellitus; Diet; Gene Expression; Gene Targeting; Glucose; Human; In Vitro; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Knock-out; Knowledge; Lead; Length; Link; LoxP-flanked allele; Mediating; Metabolic Pathway; Metabolism; Mitochondria; Mitogens; Mus; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidative Stress; Oxygen Consumption; Pathology; Pathway interactions; Pharmacology; Positioning Attribute; Production; Proliferating; Protein Isoforms; Response Elements; Rodent; Role; SCID Mice; Streptozocin; Stress; Testing; Therapeutic; Transplantation; antioxidant enzyme; cell regeneration; diabetic; diabetic patient; gene therapy; glucose metabolism; in vivo; inhibitor/antagonist; islet; novel; overexpression; response; targeted treatment; therapeutic target; therapy resistant; transcription factor

Summary It is estimated that 30-60 million Americans with Type I or Type 2 diabetes would benefit from therapies that promote expansion and enhance protection of functional beta cell mass. However, human beta cells are stubbornly resistant to therapies that would safely expand beta cell mass in diabetic patients. Thus there is an urgent need to identify and exploit new pathways to safely expand beta cell mass. Beta cells proliferate as a natural adaptive response to increased demand for insulin, and glucose itself is an effective beta cell mitogen. Here, we will explore an exciting new pathway in beta cells, the antioxidant Nrf2 pathway, that we recently found is necessary for and augments glucose-stimulated beta cell proliferation. We have been studying glucose-stimulated gene expression for nearly two decades and have found that carbohydrate response element binding protein (ChREBP), a glucose-sensing transcription factor, is required for glucose-stimulated beta cell proliferation. Surprisingly, we also found that overexpression of the full length ChREBPα isoform amplifies, by 2 to 3-fold, rodent and human glucose-stimulated beta cell proliferation, without cell death. Our preliminary data demonstrate that ChREBPα overexpression reprograms metabolism to provide anabolic building blocks for proliferation. Remarkably, ChREBPα increases mitochondrial biogenesis, oxygen consumption rates, and ATP production. Functionally, pretreatment with ChREBPα enhances transplantation outcomes of human islets in STZ-treated NOD.SCID mice. Since gene therapy maneuvers that increase ChREBPα abundance are not practical, we focused on the pathways responsible for the remarkable ChREBPα-mediated anabolic effect. We found that the ChREBPα-mediated increase in beta cell proliferation requires the activation of the antioxidant Nrf2 pathway. Nrf2 also enhances mitochondrial content and activity, and increases anabolic metabolism. Furthermore, activation of Nrf2 is necessary for normal glucose-stimulated or adaptive beta cell proliferation, in vitro and in vivo. Strikingly, increased expression of Nrf2 is sufficient to drive rodent beta cell proliferation on a standard chow diet in vivo, and human beta cell proliferation in vitro, even in low concentrations of glucose. Importantly, several pharmacological Nrf2 activators are either approved or being tested in clinical trials for a variety of pathologies, but none address beta cell biology. Thus, Nrf2 performs a previously unrecognized critical role in the adaptive expansion of beta cells that may be exploited therapeutically. The current proposal will test the exciting hypothesis that Nrf2 increases mitochondrial and anabolic function in beta cells providing both increased capacity to proliferate and increased protection from oxidative stress. We will: 1) Elucidate the role of Nrf2 in the adaptive expansion of beta cell mass; 2) Establish whether increasing or decreasing Nrf2 alters human islet transplantation outcomes. 3) Explore the mechanisms by which Nrf2 promotes glucose-stimulated proliferation. !

概括 据估计，拥有I型或2型糖尿病的3,6000万美国人将受益于疗法 促进功能β细胞量的扩展和增强保护。但是，人类beta细胞是 对糖尿病患者中可以安全扩大β细胞量的疗法具有固执的抗性。有一个 迫切需要识别和利用新的途径以安全扩展β细胞量。 β细胞随着 自然对增加胰岛素需求的反应，葡萄糖本身是一种有效的β细胞丝裂原。 在这里，我们将探索我们最近的抗氧化剂NRF2途径中令人兴奋的新途径 发现对葡萄糖刺激的β细胞增殖必不可少。我们一直在学习 葡萄糖刺激的基因表达近二十年，发现碳氢气反应 葡萄糖刺激的元素结合蛋白（CHREBP）是一种葡萄糖感应转录因子 β细胞增殖。令人惊讶的是，我们还发现全长Chrebpα同工型的过表达 放大器，啮齿动物和人类葡萄糖刺激的β细胞增殖的2至3倍，无细胞死亡。我们的 初步数据表明，Chrebpα的过表达重新编程新陈代谢以提供合成代谢 建立扩散的基础。值得注意的是，Chrebpα增加线粒体生物发生，氧气 消费率和ATP生产。在功能上，用CHREBPα进行预处理可增强移植 STZ处理的点头小鼠中人类胰岛的结果。由于基因治疗动作增加了 Chrebpα抽象不实用，我们专注于负责的途径 CHREBPα介导的合成代谢作用。我们发现Chrebpα介导的β细胞增殖增加 需要激活抗氧化剂NRF2途径。 NRF2还增强了线粒体含量和活性， 并增加了代谢代谢。此外，NRF2的激活对于正常葡萄糖刺激是必需的 或自适应β细胞增殖，体外和体内。令人惊讶的是，NRF2的表达增加足以 在体内驱动啮齿动物β细胞的增殖，并在体内驱动啮齿动物β细胞，并在体外驱动人β细胞增殖， 即使是低浓度的葡萄糖。重要的是，几种药物NRF2激活剂是 在临床试验中批准或接受了各种病理的测试，但没有针对Beta细胞生物学的研究。那， NRF2在β细胞的适应性膨胀中扮演以前未识别的关键作用 理论上被利用。当前的建议将检验NRF2增加的令人兴奋的假设 β细胞中的线粒体和合成代谢功能提供了增殖和增加的能力 防止氧化应激。我们将：1）阐明NRF2在Beta细胞自适应膨胀中的作用 大量的; 2）确定增加或减少的NRF2是否会改变人类胰岛移植结果。 3） 探索NRF2促进葡萄糖刺激的增殖的机制。 呢