Osteoprotegerin and the Pancreatic Beta Cell

 描述（由申请方提供）：糖尿病由内源性功能性胰腺β细胞质量减少引起。因此，本领域的优先事项是鉴定在体内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细胞中催乳素的一个新的下游靶点。初步研究表明，OPG在体内可诱导内源性啮齿类动物β细胞复制，在体外可诱导人β细胞增殖，可延缓小鼠1型糖尿病的发病，并可提高人β细胞抵抗糖脂毒性和甜菜碱诱导的细胞死亡的存活率。OPG是一种可溶性诱饵受体。其通过与其内源性靶点核因子κ B受体激活因子（RANK）配体（RANKL）或肿瘤坏死因子相关凋亡诱导配体（TRAIL）结合，并抑制其与相应受体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狄诺塞单抗和一种仅特异性抑制RANKL/RANK通路的单克隆抗体进一步证实了该通路的重要性。Denosumab还可增强人β细胞增殖和存活。基于累积证据，我们假设OPG和Denosumab通过抑制RANKL/RANK通路，在应激/需求增加的条件下对β细胞产生显著的治疗、生理和机制影响。我们将通过以下特定目的检验我们的假设：SA 1：评估在应激和需求增加的病理生理条件下OPG对啮齿动物和人β细胞的体内治疗潜力。SA 2：研究RANKL/RANK通路在β细胞中的生理作用。SA 3：了解OPG及其伴侣在啮齿动物和人β细胞中的调节和细胞内作用机制。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潜力。基于有说服力的初步数据，本申请中提出的研究是新颖的，及时的，有前途的，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预防潜力。

 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.