Targeting multiple Wnt inhibitors for synergistic anabolic action in the skeleton

靶向多种 Wnt 抑制剂以在骨骼中发挥协同合成代谢作用

• 批准号: 10588177
• 负责人: Roy Byungjun Choi
• 金额: $ 1.9万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10588177
• 关键词: Adult; Age; Aging; Anabolic Agents; Animals; Antibodies; Area; Binding; Biology; Bone Tissue; Breeding; Compensation; Competence; Curiosities; Cysteine; Data; Databases; Deterioration; Disabled Persons; Disease; Dose; Dual-Energy X-Ray Absorptiometry; Elderly; Exhibits; FDA approved; Family; Future; Genes; Genetic; Genome; Gerontology; Hand; Health; Heterozygote; High Risk Woman; High-Throughput Nucleotide Sequencing; Histology; Human; Individual; Informatics; Institution; Joints; Knock-out; Knockout Mice; Lead; Measures; Mechanics; Mediating; MicroRNAs; Modeling; Mus; Musculoskeletal; Mutation; Osteocytes; Osteoporosis; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Phenotype; Population; Postmenopause; Program Description; Property; Proteins; Public Health; Reagent; Risk; Skeleton; Testing; Training; Training Activity; Training Programs; Up-Regulation; WNT Signaling Pathway; Woman; Work; aged; antibody test; beta catenin; biomechanical test; bone; bone cell; bone health; bone mass; candidate identification; cardiovascular disorder risk; career; clinical efficacy; cortical bone; design; efficacy evaluation; experimental study; fracture risk; genomic locus; high risk; improved; inhibiting antibody; inhibitor; interest; large datasets; miRNA expression profiling; middle age; mouse genetics; mouse model; mutant; mutant mouse model; neutralizing antibody; parathyroid hormone-related protein; pharmacologic; pre-clinical; prevent; receptor; response; side effect; skeletal; substantia spongiosa; synergism; tool; training opportunity; transcriptome sequencing

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.

项目摘要/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- 更年期女性。人们对使用合成代谢药物治疗低骨量疾病的兴趣与日俱增 抗分解代谢的方法，其中的选择非常少。最近，FDA批准了第一个骨Anabol- PTH/PTHrP类以外的IC制剂-Evenity(Romosozumab)-用于治疗骨折高危患者。 该抗体抑制分泌的硬化素，阻止其与Wnt共受体结合和拮抗。 LRP5和LRP6。其结果是刺激了下游的β-连环蛋白途径，最终促进了合成代谢 在骨组织中的作用。然而，罗莫佐单抗的不良副作用，包括增加心血管风险- 血管疾病，是在III期临床试验中发现的，促使FDA分配了一个黑匣子 警告“给Romo，提醒处方者和患者注意风险。我的研究生学习将集中在 硬化素抑制作用要强得多，特别是在皮质骨中，因此剂量低得多的制剂 需要达到相同(或更好)的反应，同时将副作用降至最低。我会调查这个反对意见- 通过检测Wise抑制(另一种分泌的半胱氨酸结蛋白)协同免疫的能力。 证明硬化素抗体介导的皮质骨量增加。一种类似的策略，使用硬化蛋白和Dkk1联合 抑制，对于协同改善松质骨是非常有效的。我要测试一下硬化素/Dkk1 结合在一个老化模型中。通过申请表中描述的培训计划，我将获得收益- 擅长进行动物药物研究，研究突变小鼠模型，进行大量终点分析， 高通量测序、microRNA图谱分析、大数据集分析和翻译老化研究 老鼠。这些培训机会将通过3个具体目标实现：(目标1)确定 SOST和WISE共缺失/共抑制的骨合成代谢协同作用；(目标2)确定变化 当Sost/skerostin被禁用时，分泌的Wnt抑制物(和其他家族)在骨细胞中的表达；以及 (目的3)确定硬化素和Dkk1联合抑制在改善衰老松质骨中的疗效。 模特。我预计这些活动和追求除了 申请，将大大增强我在学术机构领导独立科学事业的能力- 辅导，重点关注恶化人类健康的肌肉骨骼生物学问题。

项目成果

Sostdc1 Suppression in the Absence of Sclerostin Potentiates Anabolic Action of Cortical Bone in Mice.

在缺乏硬化素的情况下抑制 Sostdc1 可增强小鼠皮质骨的合成代谢作用。

• DOI: 10.1002/jbmr.4798
• 发表时间: 2023
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Choi,RoyB;Hoggatt,AprilM;Horan,DanielJ;Rogers,EmilyZ;Loots,GabrielaG;Robling,AlexanderG
• 通讯作者: Robling,AlexanderG

Targeting Sclerostin and Dkk1 at Optimized Proportions of Low-Dose Antibody Achieves Similar Skeletal Benefits to Higher-Dose Sclerostin Targeting in the Mature Adult and Aged Skeleton.

• DOI: 10.14336/ad.2022.0315
• 发表时间: 2022-12-01
• 期刊: AGING AND DISEASE
• 影响因子: 7.4
• 作者: Choi, Roy B;Hoggatt, April M;Horan, Daniel J;Rogers, Emily Z;Hong, Jung Min;Robling, Alexander G
• 通讯作者: Robling, Alexander G