BLRD Research Career Scientist Award Application

骨质疏松症（多孔性骨病）是一种骨骼疾病，可对许多美国人造成衰弱影响。 老兵据估计，4400万美国人，即50岁及以上人口的55%， 目前有骨折的危险改善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。拟议 研究利用导致非常高的骨量的人类疾病。这些高血压的遗传原因 骨质量疾病-颅管骨肥厚、皮质骨肥厚、硬化性骨质疏松、货车Buchem's 疾病-提供了如何在骨质疏松症患者中操纵骨量以改善其 骨骼健康和预防骨折。许多高骨量相关疾病是由以下原因引起的： 一种叫做"Wnt"的细胞信号通路的突变。因此，操纵Wnt途径具有很大的希望， 来改善骨骼健康该途径作为治疗靶点特别有吸引力，因为它可以 可以被操纵以增加新骨形成，而不是简单地防止进一步的骨丢失。长期 所提出的项目的目标是双重的：首先，我们试图了解Wnt的分泌抑制剂是如何 信令作为协调单元（即，环境），通过调节它们的表达水平， 调整单元的构件（例如，禁止或删除）。这些调整在成员中的表达 的环境代表主要的目标机会，制定大的变化，在骨合成代谢行动，因为我们的 支持数据显示。我们还试图了解这种Wnt抑制剂环境如何控制合成代谢作用 机械负荷-一个强有力的合成代谢刺激，有持久的好处，骨骼。我们寻求 了解抑制环境的某些成员是否起到"归巢信号"的作用，以确保新的 骨被添加到最需要的地方--骨的高应变区域，而不是添加到 是不需要的-骨的低应变区域。我们的数据再次表明，Wnt抑制环境 在这一过程中起着重要作用。我们申请的第二个目标是进行功能研究 靶向Wnt抑制剂环境，其直接适用于患者的未来治疗方法。 骨消耗状况，如机械废用（例如，卧床休息，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Wnt抑制剂表达的变化进行了测量， 废用和糖皮质激素暴露，我们假设，"代偿环境"的四个Wnt通道-Sost， Dkk1、sFrp4和Wise通过未知的机制协调，以防止存在以下物质时的合成代谢作用： 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消耗条件下的小鼠的合成代谢活性。如果是这样，这些研究 将对旨在治疗废用退伍军人的治疗方法的设计产生深远的影响， 糖皮质激素引起的骨质疏松我们将进行的另一项功能研究也利用了 Wnt抑制剂环境的生物学，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抑制剂产生显著合成代谢反应所需的抗体 这是补偿环境的一部分。我们已经证明，我们可以大大增加 Dkk1抗体的合成代谢功效，如果我们在Sost抑制的存在下使用它。我们发现了另一种抑制剂， 也可能参与补偿-α/β-水解酶超家族的一个分泌成员， 笔记我们预期使用低得多剂量的抗体会产生显著的骨合成代谢作用， 同时阻断其他辅助Wnt抑制剂。在这一更新Merit应用程序中，我们解决这些问题 问题，以确定新的方法来改善骨骼健康的退伍军人人口， 一般来说是公开的。

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.