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

基本信息

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
项目类别：
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

项目摘要

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/摘要低骨肿块是一个主要的公共卫生问题，尤其是在老年和中年和中年更年期的妇女。使用合成代谢而不是抗代谢方法，几乎没有选择。最近，FDA批准了第一个骨Anabol- PTH/PTHRP类别外的IC代理（弱点（Romosozumab））治疗患有骨折风险的患者。该抗体抑制了分泌的硬化素，防止其结合并拮抗Wnt共受体 LRP5和LRP6。结果是刺激下游β-catenin途径，最终是合成代谢在骨组织中作用。但是，romosozumab的不良副作用，包括增加心脏风险在第三阶段临床试验中发现了血管疾病，促使FDA分配了“黑匣子” 警告”向罗莫（Romo 硬化蛋白抑制更大的潜力，尤其是在皮质骨中，因此剂量的剂量要低得多需要达到相同（或更好的）响应，同时最大程度地减少副作用。我将调查这个oppor- 通过测试明智抑制（另一种分泌的半胱氨酸结蛋白）的能力来协同效果证明皮质中的硬化蛋白抗体介导的骨骼增益。类似的策略，使用硬化蛋白和DKK1共同抑制作用，对于协同改善取消骨的高效效率高。我将测试Sclerostin/dkk1 衰老模型的组合。通过应用程序中描述的培训计划，我将获得专业进行动物药物研究，使用突变小鼠模型，大量终点分析的效率，高吞吐量测序，microRNA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个特定目标实现：（目标1）确定 SOST和WISE共同删除/共抑制的协同骨代谢作用；（目标2）确定更改在残疾/硬化蛋白被禁用时，分泌的Wnt抑制剂（和其他家庭）的骨细胞表达中；和（AIM 3）确定硬化蛋白和DKK1共同抑制在改善衰老中取消骨骼的效率模型。我期望这些活动和追求以及其他培训活动应用将大大增强我在学术研究所的独立科学职业的能力 - 专注于决定人类健康的肌肉骨骼生物学问题。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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