BLRD Research Career Scientist Award Application

骨质疏松症(多孔性骨病)是一种骨骼疾病，可对许多美国人产生衰弱作用 退伍军人。据估计，有4400万美国人，即55%的50岁及以上的人， 目前有骨质疏松性骨折的风险。改善这种疾病的治疗方案需要更大的 了解控制骨代谢的细胞事件和信号通路。建议数 研究利用了导致骨量非常高的人类疾病。这些高的遗传原因 骨量疾病--颅管骨质增生症、皮质骨质增生症、硬化性骨质疏松症、范布赫姆病 疾病-提供对骨质疏松症患者如何控制骨量以改善他们的 保持骨骼健康，防止骨折。许多与高骨量相关的疾病是由 一种名为“Wnt”的细胞信号通路的突变。因此，对Wnt途径的操纵有很大的希望 改善骨骼健康。这一途径作为治疗靶点特别有吸引力，因为它可以 被操控是为了增加新骨形成，而不是简单地防止进一步的骨丢失。从长远来看 拟议项目的目标有两个：首先，我们试图了解Wnt的分泌抑制物是如何 信号作为一个协调的单位(即，环境)，通过调整它们的表达水平来发挥作用 该单元的成员被调整(例如，禁止或删除)。这些调整在成员中的表述 的环境代表着主要的靶向机会，使骨骼的合成代谢活动发生重大变化，因为我们的 支持数据表明。我们还试图了解这种Wnt抑制剂环境是如何控制合成代谢作用的 机械负荷-一种有效的合成代谢刺激，对骨骼有持久的好处。我们寻求 了解抑制性环境的某些成员是否起到“归巢信号”的作用，以确保新的 骨骼被添加到最需要它的地方--骨骼的高应变区域，而不是添加到它 是不需要的--到骨骼的低应变区域。再一次，我们的数据表明，WNT抑制环境 在这一过程中扮演着重要的角色。我们应用程序的第二个目标是进行功能研究 以Wnt抑制剂环境为靶点，这些环境直接适用于患者未来的治疗方法。 骨损耗状况，如机械性停用(例如，卧床、瘫痪)和糖皮质激素治疗(a 用于治疗炎症和免疫抑制的药物)在退伍军人中很常见。基于 我们和其他人对以下Wnt抑制物表达的变化进行了测量 停用和糖皮质激素暴露，我们假设四种Wnt抑制剂-SOST， Dkk1、sFRP4和Wise-通过未知机制协调，以防止在存在的情况下的合成代谢作用 停用糖皮质激素治疗。我们建议以不同的组合针对整个环境，以确定 我们是否能恢复暴露在这些骨质流失条件下的小鼠的合成代谢活动。如果是这样，这些研究 将对旨在治疗废用退伍军人的疗法的设计产生深远的影响--以及 糖皮质激素引起的骨量不足。我们将进行的另一项功能研究也利用了 Wnt抑制剂的生物学环境，是为了确定我们是否可以减少Sost的剂量/体积 通过额外阻断辅助Wnt抑制物而产生显著合成代谢反应所需的抗体 这些都是补偿环境的一部分。我们已经证明，我们可以显著提高 如果我们在SOST抑制的情况下使用Dkk1抗体，它的合成代谢效率。我们发现了另一种抑制剂 也可能参与补偿-α/β-水解酶超家族中的一个秘密成员，称为 诺图姆。如果我们使用剂量低得多的抗体，我们预计会有显著的骨合成代谢效应 同时阻断其他辅助性Wnt抑制剂。在此续订奖励申请中，我们解决了以下问题 问题，以确定在退伍军人中改善骨骼健康的新方法，以及在 一般都是公共的。

Osteoporosis (porous bone disease) is a disease of the skeleton that can have debilitating effects on many US veterans. An estimated 44 million Americans, or 55 percent of the people 50 years of age and older, are currently at risk for osteoporotic fracture. Improved treatment options for the disease require a greater understanding of the cellular events and signaling pathways that control bone metabolism. The proposed research capitalizes on human diseases that result in very high bone mass. The genetic causes of these high bone mass diseases—craniotubular hyperostosis, hyperostosis corticalis, sclerosteosis, van Buchem’s disease—provide insight into how bone mass can be manipulated in osteoporotic patients to improve their skeletal health and prevent fractures. Many of the high-bone-mass associated diseases are caused by mutations in a cell signaling pathway called “Wnt.” Thus, manipulation of the Wnt pathway holds great promise for skeletal health improvement. This pathway is particularly attractive as a therapeutic target because it can be manipulated to increase new bone formation, rather than simply prevent further bone loss. The long term goals of the proposed project are twofold: first, we seek to understand how the secreted inhibitors of Wnt signaling function as a coordinated unit (i.e., a milieu), by adjusting their expression levels when other members of the unit are adjusted (e.g., inhibited or deleted). Those adjustments in expression in the members of the milieu represent prime targeting opportunities to enact large changes in anabolic action in bone, as our supporting data suggest. We also seek to understand how this Wnt inhibitor milieu controls the anabolic action of mechanical loading—a potent anabolic stimulus that has lasting benefits to the skeleton. We seek to understand whether certain members of the inhibitory milieu function as “homing signals” to ensure that new bone is added where it is needed most – to the high strain regions of the bone, and that it is not added where it is not needed – to the low strain regions of the bone. Again, our data suggest that the Wnt inhibitory milieu plays a significant role in this process. Our second goal of the application is to conduct functional studies targeting the Wnt inhibitor milieu, that have direct applicability to future therapeutic approaches in patients. Bone wasting conditions such as mechanical disuse (e.g., bedrest, paralysis) and glucocorticoid therapy (a drug used for treating inflammation and immunosuppression) are common among veterans. Based on measurements we and others have made regarding the changes in expression of Wnt inhibitors following disuse and glucocorticoid exposure, we hypothesize that the “compensatory milieu” of four Wnt inhibitors–Sost, Dkk1, sFrp4, and Wise—coordinate via unknown mechanisms to prevent anabolic action in the presence of disuse glucocorticoid therapy. We propose to target the entire milieu in different combinations, to determine whether we can restore anabolic activity in mice exposed to these bone wasting conditions. If so, those studies would have far-reaching implications for the design of therapies aimed at treating veterans with disuse- and glucocorticoid-induced bone deficiencies. Another functional study we will undertake, which also capitalizes on the biology of the Wnt inhibitor milieu, is to determine whether we can reduce the dose/volume of Sost antibody required to generate a significant anabolic response by additionally blocking accessory Wnt inhibitors that are part of the compensatory milieu. We have already shown that we can dramatically increase the anabolic efficacy of Dkk1 antibody if we use it in the presence of Sost inhibition. We found another inhibitor that also might participate in compensation – a secreted member of the α/β-hydrolase superfamily known as Notum. We anticipate a significant osteoanabolic effect using much lower doses of antibody if we simultaneously block other accessory Wnt inhibitors. In this renewal Merit application, we address these questions in order to identify new ways to improve bone health among the veteran population, and among the public in general.