Osteoprotegerin and the Pancreatic Beta Cell

 描述(由申请人提供)：糖尿病是内源性功能性胰腺β细胞团减少所致。因此，该领域的当务之急是寻找在体内β细胞压力和需求增加的条件下，促进功能性β细胞生长、再生和存活的药物。我们最近发现骨保护素(OPG)是β细胞中一个新的乳素下游靶点。初步研究表明，OPG可在体内诱导内源性啮齿动物β细胞复制，在体外诱导人β细胞增殖，延缓小鼠1型糖尿病的发生，并能提高人β细胞抵抗糖中毒和细胞因子诱导的细胞死亡的存活能力。OPG是一种可溶性诱饵受体。它通过与其内源性核因子kappaB受体激活剂配体(RANKL)或肿瘤坏死因子相关的凋亡诱导配体(TRAIL)结合，并抑制它们与各自的受体RANK和死亡受体的相互作用而发挥作用。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FDA批准的治疗骨质疏松症的药物Denosumab和仅特异性抑制RANKL/RANK途径的单抗进一步证实了这一途径的重要性。Denosumab还可以促进人β细胞的增殖和存活。根据累积的证据，我们假设在压力/需求增加的条件下，通过抑制RANKL/RANK通路，OPG和Denosumab将对β细胞产生显著的治疗、生理和机制影响。我们将通过以下具体目标来验证我们的假设：SA 1：评估OPG在应激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：探讨RANKL/RANK信号通路在β细胞中的生理作用。SA 3：了解OPG及其伴侣对啮齿动物和人β细胞的调节作用及其细胞内作用机制。这些发现的临床影响来自于测试这一途径在 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点，以及将骨质疏松症药物Denosumab重新用于治疗糖尿病的可能性。本申请中提出的研究是新颖、及时和有前景的，基于有说服力的初步数据，具有很高的成功潜力。因此，这些研究的积极结果可能具有显著的翻译潜力。

 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.