Osteoprotegerin and the Pancreatic Beta Cell

骨保护素和胰腺β细胞

• 批准号: 9201325
• 负责人: Rupangi C Vasavada
• 金额: $ 40.87万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9201325
• 关键词: Amination; Amines; B Cell Proliferation; Beta Cell; Binding; Biology; Cations; Cell Death; Cell Survival; Cells; Cellular Stress; Cessation of life; Clinical; Data; Development; Diabetes Mellitus; Diabetic mouse; FDA approved; Future; Goals; Growth; Human; Immune; In Vitro; Insulin-Dependent Diabetes Mellitus; Knowledge; Lead; Ligands; Mediating; Metabolic; Modeling; Monoclonal Antibodies; Mus; NF-kappa B; Natural regeneration; Necrosis; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Osteoporosis; Outcome; Outcome Study; Pancreas; Pancreatectomy; Pathway interactions; Pharmaceutical Preparations; Physiological; Regulation; Reticulum; Rodent; Role; Signal Pathway; Stimulus; Stress; Structure of beta Cell of islet; TNF gene; TRANCE protein; Testing; Therapeutic; Time; Tumor necrosis factor receptor 11b; apolipoprotein D; base; bone; cell growth; cytokine; drug development; endoplasm; improved; in vivo; insulin dependent diabetes mellitus onset; islet; man; novel; public health relevance; receptor; success; translational impact

 DESCRIPTION (provided by applicant): Diabetes results from a reduction in endogenous functional pancreatic βcell mass. Therefore, a priority in the field is to identify agents that enhance functional βcell growth, regeneration, and survival, under conditions of increased βcell stress and demand in vivo. We have recently discovered osteoprotegerin (OPG) to be a novel downstream target of lactogens in the βcell. Preliminary studies indicate that OPG can induce endogenous rodent βcell replication in vivo, human βcell proliferation in vitro, delay onset of Type 1 diabetes in mice, and improve human βcell survival against glucolipotoxicityand cytokineinduced cell death. OPG is a soluble decoy receptor. It acts by binding to its endogenous targets receptor activator of nuclear factor kappaB (RANK) ligand (RANKL) or tumor necrosis factor related apoptosisinducing ligand (TRAIL), and inhibiting their interaction with the respective receptors, RANK and death receptor. In βcells, we found OPG induces human βcell proliferation through inhibition of the RANKL/RANK interaction. We further confirmed the importance of this pathway using Denosumab, an FDAapproved drug for osteoporosis, and a monoclonal antibody that specifically inhibits only the RANKL/RANK pathway. Denosumab also enhances human βcell proliferation and survival. Based on the cumulative evidence we hypothesize that OPG and Denosumab through inhibition of the RANKL/RANK pathway will have a significant therapeutic, physiologic, and mechanistic impact on the βcell, under conditions of increased stress/demand. We will test our hypothesis through the following Specific Aims: SA 1: To assess the in vivotherapeutic potential of OPG on rodent and human βcells under pathophysiologic conditions of increased stress and demand. SA 2: To establish the physiologic role of the RANKL/RANK pathwayin βcells. SA 3: To understand the regulation and the intracellular mechanism of action of OPG and its partners in rodent and human βcells. The clinical impact of the findings come from testing the effects of this pathway in vivo, in models of increased metabolic demand on rodent and human βcells, identifying downstream targets for future drug development, and the potential for repurposing an osteoporosis drug, Denosumab, for the treatment of diabetes. The studies proposed in this application are novel, timely, and promising, with a high potential for success, based on the persuasive preliminary data. Thus, positive outcomes from these studies could have significant translationalpotential.

 描述（由申请人提供）：糖尿病是由内源性功能性胰腺β细胞量减少引起的。因此，该领域的首要任务是鉴定在体内β细胞应激和需求增加的条件下增强功能性β细胞生长、再生和存活的试剂。我们最近发现骨保护素 (OPG) 是 β 细胞中催乳素的新下游靶标。初步研究表明，OPG 可诱导内源性啮齿动物 β 细胞在体内复制、在体外诱导人 β 细胞增殖、延缓小鼠 1 型糖尿病的发病，并提高人 β 细胞对糖脂毒性和细胞因子诱导的细胞死亡的存活率。 OPG 是一种可溶性诱饵受体。它通过与其内源性靶标受体激活剂核因子 kappaB (RANK) 配体 (RANKL) 或肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 结合，并抑制它们与各自受体、RANK 和死亡受体的相互作用来发挥作用。在 β 细胞中，我们发现 OPG 通过抑制 RANKL/RANK 相互作用来诱导人 β 细胞增殖。我们使用狄诺塞麦（FDA 批准的治疗骨质疏松症的药物）和仅特异性抑制 RANKL/RANK 通路的单克隆抗体进一步证实了该通路的重要性。 Denosumab 还可以增强人类 β 细胞的增殖和存活。基于累积的证据，我们假设在压力/需求增加的情况下，OPG 和狄诺塞麦通过抑制 RANKL/RANK 通路将对 β 细胞产生显着的治疗、生理和机制影响。我们将通过以下具体目标检验我们的假设： SA 1：评估 OPG 在压力和需求增加的病理生理条件下对啮齿动物和人类 β 细胞的体内治疗潜力。 SA 2：确定 RANKL/RANK 通路在 β 细胞中的生理作用。 SA 3：了解 OPG 及其伙伴在啮齿动物和人类 β 细胞中的调节和细胞内作用机制。研究结果的临床影响来自于测试该通路在 在啮齿动物和人类 β 细胞代谢需求增加的模型中，确定未来药物开发的下游靶标，以及重新利用骨质疏松症药物 Denosumab 治疗糖尿病的潜力。基于有说服力的初步数据，本申请中提出的研究新颖、及时且有前景，具有很高的成功潜力。因此，这些研究的积极成果可能具有显着的转化潜力。