BLR&D Research Career Scientist Award Application

骨质疏松症(多孔性骨病)是一种骨骼疾病，可对许多人产生衰弱作用 美国退伍军人。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多的- 了解控制骨代谢的细胞事件和信号通路。我的研究计划 利用导致骨量非常高的人类疾病。这些高骨的遗传原因 大量疾病--颅管骨质增生症、硬化症、范布赫姆病--提供了对如何 骨质疏松症患者可以通过控制骨量来改善骨骼健康，预防骨折。 许多与高骨量相关的疾病是由细胞信号通路突变引起的 “WNT.”因此，操纵Wnt通路对改善骨骼健康大有可为。这条路- Way作为治疗靶点特别有吸引力，因为它可以被操纵来增加新的骨骼- 而不是简单地防止进一步的骨丢失(这是目前可用的FDA中除一种之外的所有药物- 经批准的治疗方法有效)。我的研究计划的长期目标有两个：第一，我们寻求低于- 了解分泌的Wnt信号抑制物如何通过调节作为一个协调单位(即，环境)发挥作用 当该单元的其他成员被调整(例如，被禁止或删除)时，它们的表达水平。那些调整- 在环境成员中的表达代表了最好的目标制定机会 正如我们的支持数据所显示的，骨骼中合成代谢活动的变化。我们也试图理解这是如何 WNT抑制剂Amieu控制机械负荷的合成代谢作用--一种有效的合成代谢刺激，具有 对骨骼有持久的益处。我们试图了解抑制性环境功能的某些成员是否- 作为“归巢信号”，以确保新的骨骼被添加到最需要它的地方--高应变区域 它不会在不需要的地方添加--添加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发挥着重要作用。我们的第二个目标是- 针对Wnt抑制剂环境的导管功能研究，对未来的治疗AP具有直接适用性。 病人身上的问题。骨损耗情况，如机械性废用(如卧床休息、瘫痪)和血糖过高 皮质激素治疗(一种用于治疗炎症和免疫抑制的药物)在Veter- 答案是。根据我们和其他人对Wnt抑制基因表达变化的测量- 在停用和糖皮质激素暴露后，我们假设四个WNT的“代偿环境” 抑制物-SOST、Dkk1、sFRP4和WISE-通过未知的机制协调以防止合成代谢作用 停用糖皮质激素治疗的存在。我们正在积极地以不同的组合来瞄准整个环境- 为了确定我们是否能恢复暴露在这些骨损耗条件下的小鼠的合成代谢活动- 特兹。如果是这样的话，这些方法将对旨在治疗的疗法的设计产生深远的影响。 退伍军人因停用和糖皮质激素导致的骨缺乏症。我们定义的另一个目标，就是 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剂量/ 通过额外阻断Aces而产生显著的合成代谢反应所需的SOST抗体的体积- Sory Wnt抑制剂是代偿环境的一部分。我们已经证明，我们可以戏剧性地 如果在存在SOST抑制的情况下使用Dkk1抗体，则可提高其合成代谢效率。我们预计会有一个 如果我们同时阻断其他通路，使用低得多剂量的抗体就会产生显著的骨合成代谢效应- RY WNT抑制剂。所描述的整个研究计划解决了这些问题，以确定新的 如何在退伍军人和普通公众中改善骨骼健康。

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 under- standing of the cellular events and signaling pathways that control bone metabolism. My research program capitalizes on human diseases that result in very high bone mass. The genetic causes of these high bone mass diseases—craniotubular hyperostosis, 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 path- way is particularly attractive as a therapeutic target because it can be manipulated to increase new bone for- mation, rather than simply prevent further bone loss (which is how all but one of the currently available FDA- approved therapies work). The long term goals of my research program are twofold: first, we seek to under- stand 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 adjust- ments 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 func- tion 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 is to con- duct functional studies targeting the Wnt inhibitor milieu, that have direct applicability to future therapeutic ap- proaches in patients. Bone wasting conditions such as mechanical disuse (e.g., bedrest, paralysis) and gluco- corticoid therapy (a drug used for treating inflammation and immunosuppression) are common among veter- ans. Based on measurements we and others have made regarding the changes in expression of Wnt inhibi- tors 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 are actively targeting the entire milieu in different combina- tions, to determine whether we can restore anabolic activity in mice exposed to these bone wasting condi- tions. If so, those approaches would have far-reaching implications for the design of therapies aimed at treat- ing veterans with disuse- and glucocorticoid-induced bone deficiencies. Another goal we have defined, 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 acces- sory 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 anticipate a significant osteoanabolic effect using much lower doses of antibody if we simultaneously block other accesso- ry Wnt inhibitors. The overall research program described addresses these questions in order to identify new ways to improve bone health among the Veteran population, and among the public in general.