Harnessing the anabolic potential of Wnt signaling to improve bone health

利用 Wnt 信号的合成代谢潜力来改善骨骼健康

• 批准号: 10514588
• 负责人: ALEXANDER G ROBLING
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514588
• 关键词: Address; Adult; Adverse event; Affect; Age; Age Years; Alcohol consumption; Amendment; American; Award; Basic Science; Bed rest; Binding; Biomechanics; Bone Diseases; Bone Tissue; C57BL/6 Mouse; Cardiovascular system; Cell Lineage; Cells; Complex; Cre driver; Data; Defect; Development; Diagnosis; Dioxins; Disease; Effector Cell; Engineering; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Erinaceidae; Event; Exposure to; FDA approved; Fatty Acids; Fatty acid glycerol esters; Fracture; Future; Gene Expression; Genetic Transcription; Glucocorticoids; Glycoproteins; Goals; Health; High Prevalence; High Risk Woman; Hip Fractures; Homeostasis; Human; Inflammatory Bowel Diseases; Internships; Knock-out; Knockout Mice; Label; Ligands; Limb Bud; Long-Term Care; LoxP-flanked allele; Measures; Mechanics; Mediating; Mesenchymal; Methods; Modeling; Monkeys; Mus; Muscle; Mutant Strains Mice; Mutation; Myocardial Infarction; Organ Transplantation; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteopenia; Osteoporosis; Paralysed; Pathway interactions; Patients; Persons; Phenotype; Population; Porosity; Post-Traumatic Stress Disorders; Postmenopause; Pre-Clinical Model; Predisposition; Prisoner; Property; Proteins; Rattus; Regulation; Research; Rheumatoid Arthritis; Risk; Risk Factors; Serum; Serum Markers; Services; Signal Pathway; Signal Transduction; Site; Skeleton; Smoking; Steroids; Stroke; Tail; Tetrachlorodibenzodioxin; Therapeutic; Veterans; Vietnam; War; Wasting Syndrome; Woman; Work; adjudication; agent orange; bone; bone health; bone loss; bone mass; bone metabolism; bone preservation; carboxylesterase; cardiovascular risk factor; cell type; cortical bone; experimental study; fracture risk; improved; inhibitor; lifestyle factors; medication safety; men; military veteran; mortality; neutralizing antibody; novel; osteoclastogenesis; osteoporosis with pathological fracture; pharmacologic; phase III trial; post-market; programs; radiological imaging; receptor; response; side effect; skeletal; skeletal disorder; success; therapy development; tumor; wasting

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 a recently identified secreted inhibitor of Wnt glycoproteins. The long-term goal of the proposed project is to investigate whether targeting a new, secreted inhibitor of Wnt signaling—Notum--can improve bone properties and reduce fracture susceptibility. In the first aim we propose to determine the cell type in which Notum inhibition exerts its effects on bone homeostasis, by crossing conditional Notum mutant mice to different Cre drivers that are active during different stages of the mesenchymal cell lineage. We will also look the gene expression changes induced by Notum inhibition to see if the canonical Wnt pathway, the noncanonical Wnt pathway, the Hedgehog pathway, or some other pathway, is primarily affected. We will also identify downstream nodes in the pathways altered by Notum inhibition, to see if there are more readily targetable effectors of the HBM phenotype induced by Notum inhibition. I the second aim, we will conduct functional studies targeting Notum, which has direct applicability to future therapeutic approaches in patients. Glucocorticoids are widely used among the veteran population for numerous conditions, including organ transplant, rheumatoid arthritis, inflammatory bowel disease, and others, but side effects are not trivial, and bone wasting is a major concern among glucocorticoid-treated patients. Likewise, mechanical disuse is a major problem among veterans, which results from long term bedrest, paralysis, and other complications. We will inhibit Notum in these preclinical models to determine whether Notum inhibition represents a viable strategy for preserving bone mass and function during two relevant bone wasting conditions. 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.

骨质疏松症（多孔骨疾病）是骨骼的疾病，可能使人衰弱 对许多美国退伍军人的影响。估计有4400万美国人，或55％的人 50岁以上的年龄较大，目前有骨质疏松性骨折的风险。改进的治疗方法 该疾病的选择需要对细胞事件和信号传导有更深入的了解 控制骨代谢的途径。拟议的研究大写了最近的 确定的Wnt糖蛋白的分泌抑制剂。拟议项目的长期目标是 调查针对新的，分泌的Wnt信号传导的抑制剂-Notum- -CAN改善 骨特性并降低断裂敏感性。在第一个目标中，我们建议确定 通过横断 有条件的不突变小鼠到不同阶段不同的CRE驱动器 间充质细胞谱系。我们还将研究基因表达的变化。 不受抑制，以查看规范的Wnt途径，非规范的Wnt途径， 刺猬途径或其他一些途径主要受到影响。我们还将确定 路径中的下游节点因抑制而改变，以查看是否更容易 NONUM抑制引起的HBM表型的靶向作用。我是第二个目标，我们 将进行针对Notum的功能研究，该研究直接适用于未来 患者的治疗方法。糖皮质激素被广泛用于退伍军人 人口在许多情况下，包括器官移植，类风湿关节炎， 炎症性肠病等 糖皮质激素治疗的患者的主要关注点。同样，机械废弃是主要的 退伍军人之间的问题，这是由长期卧床，瘫痪和其他 并发症。在这些临床前模型中，我们将抑制毫无疑问 抑制作用代表了在两个相关期间保存骨骼和功能的可行策略 浪费骨骼条件。在此续签功绩申请中，我们按顺序解决这些问题 确定新的方法来改善退伍军人人口中的骨骼健康，以及 一般公开。