Lrp5 and Lrp6 signaling in bone mechanotransduction and metabolism

骨力转导和代谢中的 Lrp5 和 Lrp6 信号传导

• 批准号: 10928976
• 负责人: ALEXANDER G ROBLING
• 金额: $ 34.87万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10928976
• 关键词: Address; Affect; Antibodies; Area; Automobile Driving; Biochemical; Biological Models; Biology; Bone Tissue; Cardiovascular Physiology; Cell Surface Proteins; Cell Surface Receptors; Cells; Clinical; Collaborations; Disease; Disparate; Exercise; Exhibits; Failure; Fracture; Gene Proteins; Goals; Health; Histologic; Human; Indiana; Investigation; Label; Ligands; Mediating; Metabolism; Microscopic; Modeling; Molecular; Molecular Biology; Molecular Target; Mus; Mutation; Osteogenesis; Osteoporosis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physical activity; Process; Program Description; Property; Research; Resistance; Resources; Risk; Role; Signal Transduction; Techniques; Therapeutic; WNT Signaling Pathway; Work; bone; bone cell; bone mass; bone strength; cardiovascular effects; cardiovascular health; gain of function mutation; improved; in vivo; innovation; interest; mechanical signal; mechanotransduction; mouse model; next generation; protein function; radiological imaging; receptor; side effect; skeletal; therapy outcome; tool; transcriptomics

The search for molecular targets and pathways that can be manipulated to improve bone properties is a highly active area of investigation. Recently, particular interest has been expressed in targeting biomolecules that can augment mechanical signaling in bone; the next generation of osteoporosis drugs is likely to work in conjunction with physical activity/loading in order to disproportionately direct new bone formation to the skeletal loci that need it most (i.e., those loci that endure the greatest strains and are at the greatest risk of failure). The WNT signaling pathway has emerged as a key regulator of bone mass and strength, but also of bone cell mechanotransduction. Recent clinical approval of the osteoporosis therapy EvenityTM (i.e., Romosozumab- aqqg) has highlighted the utility and potency of targeting the WNT pathway to improve skeletal properties and fracture resistance. However, the FDA issued a black-box label to the product because of its side effects on cardiovascular function and health. Recent work suggests that the effects of WNT stimulation on bone formation can be isolated from those on cardiovascular function, but the molecular mechanisms driving these disparate processes are completely unknown. The goal of the present is application is to understand precisely how LRP5 and LRP6—two structurally related cell surface proteins that function as WNT co-receptors—differ in their skeletal and non-skeletal contexts, with the goal of exploiting signaling differences to improve clinically based WNT therapeutic outcomes (e.g., sclerostin inhibition). Among the key questions addressed are: (1) Do LRP5 and LRP6 exhibit different predilection, or selectivity, to different WNT ligands in bone cells in vivo? (2) Does LRP5 activation trigger different downstream signaling networks than activated LRP6? (3) Among the known canonical WNTs, which activate only LRP5, only LRP6 or both? (4) Is LRP6 involved in mechanotransduction in bone (overuse and/or disuse)? (5) Can activation of LRP5 alone (through sclerostin antibody-mediated inhibition or by gain-of-function mutation in the receptor) improve bone properties to a greater extent than activation of LRP6 alone? And (6) are cardiovascular effects differentially affected by LRP5 vs LRP6 signaling (in isolation)? We will use cutting-edge mouse models, microscopic techniques, single cell and spatial transcriptomic approaches, mechanotransduction models, and radiographic/histologic/ biochemical approaches to reveal the underlying biology and therapeutic potential/differences of LRP5 and LRP6 in bone tissue. The project is a continuation of the close collaboration between the Robling (Indiana Univ.) and Warman (Harvard Univ.) labs, an extremely fruitful partnership for more than 17 yrs. We have assembled a unique combination of expertise, resources, biological models and tools, and technical innovation to elucidate and distinguish the roles of LRP5 and LRP6 in bone biology.

搜索可以操纵以改善骨特性的分子靶标和途径是高度 活跃的投资领域。最近，在靶向可能的生物分子方面表达了特别的兴趣 增强骨骼的机械信号传导；下一代骨质疏松药物可能会在 与体育锻炼/加载的联系，以使新骨形成不成比例 最需要它的基因座（即那些忍受最大压力并且最大风险失败风险的基因座）。 Wnt信号通路已成为骨质量和强度的关键调节剂，但也是骨细胞的关键调节剂 机械转导。骨质疏松疗法的最新临床批准均匀性均 AQQG）强调了针对Wnt途径以改善骨骼特性和的实用性和效力 断裂性。但是，FDA由于其副作用而发布了黑盒标签 心血管功能和健康。最近的工作表明Wnt刺激对骨骼的影响 可以与心血管功能上的形成隔离，但是驱动这些的分子机制 不同的过程是完全未知的。当前的目的是确切理解 LRP5和LRP6如何用作Wnt共受体的结构相关的细胞表面蛋白 - 差异 在其骨骼和非骨骼环境中，目的是利用信号差异以改善临床 基于WNT的治疗结果（例如，硬化蛋白抑制）。解决的关键问题包括：（1）做 LRP5和LRP6暴露于体内骨细胞中不同的Wnt配体的不同预测或选择性？ （2） LRP5激活是否会触发与激活的LRP6不同的下游信号网络？ （3） 仅激活LRP5的已知规范WNT，仅激活LRP6或两者兼而有之？ （4）涉及LRP6 骨骼的机械转导（过度使用和/或废除）？ （5）可以单独激活LRP5（通过硬化蛋白 抗体介导的抑制作用或通过接收器中的功能获得突变提高骨特性 仅比单独激活LRP6更大？ （6）受心血管效应的影响不同 LRP5与LRP6信号（分别）？我们将使用尖端的鼠标模型，微观技术，单个 细胞和空间转录组方法，机械转导模型以及射线照相/组织学/ 生化方法揭示了LRP5和 骨组织中的LRP6。该项目延续了游荡（印第安纳州）之间的密切合作 大学）和沃曼（Harman）（哈佛大学）实验室，这是一种超过17年的富有成果的伙伴关系。我们有 组装了专业知识，资源，生物模型和工具以及技术创新的独特组合 阐明和区分LRP5和LRP6在骨生物学中的作用。