Targeting multiple Wnt inhibitors for synergistic anabolic action in the skeleton

项目总结/摘要 低骨量疾病是一个主要的公共卫生问题，特别是在老年人和中年后， 更年期妇女越来越多的人对使用合成代谢而不是 抗分解代谢的方法，其中有很少的选择。最近，FDA批准了第一个骨anabol- PTH/PTHrP类别之外的ic药物-Evenity（romosozumab）-用于治疗骨折高危患者。 该抗体抑制分泌的硬化蛋白，阻止其结合并拮抗Wnt辅助受体 LRP 5和LRP 6。其结果是刺激下游β-连环蛋白途径，并最终，合成代谢 作用于骨组织。然而，romosozumab的不良副作用，包括心血管疾病风险增加， 在III期临床试验中发现了血管疾病，促使FDA分配了一个“黑匣子 警告”，提醒开处方者和患者注意风险。我的研究生课程将专注于 硬化蛋白抑制作用强得多，特别是在皮质骨中，因此， 需要达到相同（或更好）的反应，同时尽量减少副作用。我要调查这个机会- 通过测试Wise抑制（另一种分泌的半胱氨酸结蛋白）协同抑制的能力， 证明了硬化蛋白抗体介导的皮质骨增加。一个类似的策略，使用sclerostin和Dkk 1 co- 抑制，对于协同改善松质骨是高度有效的。我将测试硬化蛋白/DKK 1 在老化模型中的组合。通过在应用程序中描述的培训计划，我将获得利润- 进行动物药物研究的科学性，突变小鼠模型，许多终点分析， 高通量测序，microRNA分析，大数据集分析和翻译老化研究， 小鼠这些培训机会将通过三个具体目标实现：（目标1）确定 Sost和Wise共缺失/共抑制的协同骨合成代谢作用;（目的2）确定 当Sost/sclerostin被禁用时，分泌的Wnt抑制剂（和其他家族）的骨细胞表达;以及 (Aim 3）确定硬化素和Dkk 1共抑制在改善老化患者松质骨中的功效， 模型我预计，这些活动和追求，除了其他培训活动中所描述的 申请，将显着提高我的能力，领导一个独立的科学生涯在一个学术机构， tution，专注于恶化人类健康的肌肉骨骼生物学问题。

Project Summary/Abstract Low bone mass disease is a major public health concern, particularly among the elderly and middle-age post- menopausal women. There is growing interest in treating low bone mass disease using anabolic rather than anti-catabolic approaches, of which there are very few options. Recently, FDA approved the first bone anabol- ic agent outside of the PTH/PTHrP class—Evenity (romosozumab)—to treat patients at high risk of fracture. This antibody inhibits secreted sclerostin, preventing it from binding and antagonizing the Wnt co-receptors LRP5 and LRP6. The result is a stimulation of the downstream β-catenin pathway, and ultimately, anabolic action in bone tissue. However, unwanted side effects of romosozumab, including increased risk of cardio- vascular disease, were found during the phase III clinicals trials, prompting the FDA to assign a “black box warning” to romo, alerting prescribers and patients to the risks. My graduate studies will focus on making sclerostin inhibition much more potent, particularly in cortical bone, so that much lower doses of the agent are required to achieve the same (or better) response, while minimizing side effects. I will investigate this oppor- tunity by testing the ability of Wise inhibition (another secreted cysteine knot protein) to synergistically im- prove sclerostin antibody-mediated bone gain in the cortex. A similar strategy, using sclerostin and Dkk1 co- inhibition, is highly efficacious for synergistically improving cancellous bone. I will test the sclerostin/Dkk1 combination in an aging model. Through the training program described in the application, I will gain profi- ciency in conducting animal drug studies, working with mutant mouse models, numerous endpoint analyses, high throughput sequencing, microRNA profiling, large dataset analysis, and translational aging studies in mice. These training opportunities will be accomplished through 3 specific aims: (Aim 1) to determine the synergistic osteoanabolic action of Sost and Wise co-deletion/co-inhibition; (Aim 2) to determine the changes in osteocytic expression of secreted Wnt inhibitors (and other families) when Sost/sclerostin is disabled; and (Aim 3) to determine the efficacy of sclerostin and Dkk1 co-inhibition in improving cancellous bone in an aging model. I anticipate that these activities and pursuit, in addition to the other training activities described in the application, will significantly enhance my ability to lead an independent scientific career at an academic insti- tution, focusing on musculoskeletal biology problems that deteriorate human health.