Improving bone health by harnessing the anabolic potential of LDL receptor relate

通过利用 LDL 受体相关的合成代谢潜力来改善骨骼健康

• 批准号: 8433216
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8433216
• 关键词: Accounting; Address; Affect; Age; Age-Years; Alcohol consumption; Alleles; American; Amino Acid Substitution; Anabolism; Binding; Biological; Bone Diseases; Bone Resorption; Bone Tissue; Collection; Data; Depressed mood; Diagnosis; Dioxins; Disease; Engineering; Environmental Risk Factor; Event; Family; Fracture; Genes; Goals; Hip Fractures; Human; Implant; Intervention; Knock-in Mouse; Knock-out; Knockout Mice; LDL-Receptor Related Protein 1; LDL-Receptor Related Proteins; Lead; Light; Long-Term Care; Low Density Lipoprotein Receptor; Mediating; Missense Mutation; Modeling; Molecular Target; Mus; Mutation; Orthopedics; Osteogenesis; Osteoporosis; Pathway interactions; Patients; Phenotype; Positioning Attribute; Post-Traumatic Stress Disorders; Predisposition; Prisoner; Prosthesis; Receptor Signaling; Regulation; Reporting; Research; Resistance; Risk; Services; Signal Pathway; Signal Transduction; Skeleton; Smoking; Specificity; Surface; Testing; Tetrachlorodibenzodioxin; Tissues; Veterans; Vietnam; WNT Signaling Pathway; War; Woman; adjudication; agent orange; bone; bone cell; bone health; bone loss; bone mass; bone metabolism; cell type; extracellular; improved; in vitro activity; in vivo; lifestyle factors; loss of function mutation; men; mortality; mouse model; novel; novel strategies; osteogenic; osteoporosis with pathological fracture; receptor; stem; tool; trafficking

DESCRIPTION (provided by applicant): 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 collection of missense mutations in 2-propeller 1 of the LDL-receptor-related protein 5 (LRP5), recently identified in several human families, that have a major impact on bone mass regulation. The long term goal of the proposed project is to identify new molecular targets, yielded from novel mouse models engineered with those mutations, for pharmacologic intervention aimed at improving bone mass and reducing fracture susceptibility. LRP5 has been postulated to participate in the canonical WNT signaling cascade (e.g., GSK32-mediated modulation of 2- catenin activity) in vitro, but our recent data indicates that alterations in canonical WNT signaling might not account for the anabolic effects of the HBM mutations. Discovery of the mechanism by which Lrp5 controls bone formation would lead to new approaches for improving bone mass. In this application, we propose to determine whether 2-catenin is required for the bone formation effects of Lrp5. We will use two novel knock-in mouse models of HBM disease. These mice, which are modeled after two of the LRP5 HBM human families, have either the G171V or the A214V amino acid substitutions knocked in to Lrp5. The mutations result in very high bone mass, driven completely by increased bone formation, with no change in bone resorption. We will test whether these two mutations are associated with increased bone formation when 2- catenin is deleted. Further, we will determine whether the bone formation phenotype of Lrp5 knockout mice can be rescued by constitutive activation of 2-catenin. Subsequently, we will determine the mechanism of action for the G171V and A214V mutations, which appear to have fundamentally different effects at the cellular and tissue levels. In this Merit application, we address these questions in order to identify new Lrp5-associated anabolic targets for improving bone health.

描述（由申请人提供）： 骨质疏松症（多孔性骨疾病）是一种骨骼疾病，可能对许多美国退伍军人造成衰弱影响。据估计，4400万美国人，或55%的50岁及以上的人，目前有患骨质疏松性骨折的风险。改善这种疾病的治疗方案需要更好地了解控制骨代谢的细胞事件和信号通路。这项拟议的研究利用了LDL受体相关蛋白5（LRP 5）2-螺旋桨1中的一系列错义突变，这些错义突变最近在几个人类家族中发现，对骨量调节有重大影响。该项目的长期目标是确定新的分子靶点，这些靶点来自于用这些突变改造的新型小鼠模型，用于旨在改善骨量和降低骨折易感性的药理学干预。已经假定LRP 5参与典型的WNT信号级联（例如，GSK 32介导的2-连环蛋白活性调节），但我们最近的数据表明，经典WNT信号转导的改变可能不能解释HBM突变的合成代谢作用。Lrp 5控制骨形成的机制的发现将导致改善骨量的新方法。在本申请中，我们提出确定2-连环蛋白是否是Lrp 5的骨形成作用所必需的。我们将使用两种新的HBM疾病基因敲入小鼠模型。这些小鼠以两个LRP 5 HBM人类家族为模型，具有敲入Lrp 5的G171 V或A214 V氨基酸取代。突变导致非常高的骨量，完全由骨形成增加驱动，骨吸收没有变化。我们将测试当2-连环蛋白缺失时，这两种突变是否与骨形成增加相关。此外，我们将确定Lrp 5基因敲除小鼠的骨形成表型是否可以通过2-连环蛋白的组成性激活来挽救。随后，我们将确定G171 V和A214 V突变的作用机制，这似乎在细胞和组织水平上具有根本不同的影响。在这项Merit申请中，我们解决了这些问题，以确定新的Lrp 5相关的合成代谢靶点，以改善骨骼健康。