Center of Research Translation on Osteoporosis Bone Anabolic Therapies

骨质疏松症骨合成代谢疗法研究转化中心

• 批准号: 10404412
• 负责人: Marc Nathan Wein
• 金额: $ 169.17万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404412
• 关键词: Acceleration; Accounting; Affect; Agonist; Anabolic Agents; Anabolism; Antibodies; Antibody Therapy; Bioinformatics; Biology; Biomechanics; Bone Diseases; Bone Formation Stimulation; Bone Marrow; Bone Matrix; Bone Resorption; Cells; Center for Translational Science Activities; Clinical; Clinical Research; Cloud Computing; Communication; Communities; Data; Data Set; Disease; Epidemiology; Equilibrium; Flow Cytometry; Forteo; Genes; Genetic; Genetic Variation; Genomics; Goals; Hip Fractures; Histopathology; Human; Human Genetics; Infrastructure; Institution; International; Investigation; Knockout Mice; London; Mediating; Mesenchymal; Methods; Modeling; Molecular; Molecular Mechanisms of Action; Molecular Profiling; Monoclonal Antibodies; Mus; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Parathyroid Hormone Receptor; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Population; Postmenopausal Osteoporosis; Pre-Clinical Model; Process; Public Health; Research; Research Personnel; Risk; Role; Sampling; Testing; Therapeutic; Time; Woman; Work; aging population; bone; bone mass; cell type; college; computational platform; cortical bone; cost; experience; fracture risk; fragility fracture; gene network; human data; improved; innovation; knowledge translation; medical schools; mouse genetics; mouse model; multidisciplinary; next generation; novel; optimal treatments; parathyroid hormone (1-34); pre-clinical; progenitor; response; side effect; single-cell RNA sequencing; skeletal; skeletal stem cell; stem cell biology; stem cells; transcriptome sequencing; transcriptomics; translational research program; treatment response; treatment strategy

Project Summary – Overall Osteoporosis is a major problem in our aging population. While the pharmacological treatment of osteoporosis has advanced substantially over the past 2 decades, treatment that can truly reduce the risks of fracture to youthful levels remains elusive. Bone anabolic therapies (parathyroid hormone receptor agonists teriparatide/abaloparatide and the anti-sclerostin antibody romosozumab) represent an important component of our therapeutic armamentarium for this common, costly, serious, and debilitating disease. Without an optimized ability to stimulate bone formation, cure of osteoporosis for many patients with severe disease will not be achieved. Notably, the anabolic efficacy of our currently-used agents wanes over time for unknown reasons. The goal of the CORT is to elucidate mechanisms of action of osteoporosis anabolic therapies, and to understand why they stop working. In doing so, the CORT will accelerate translation of knowledge to improve our understanding of osteoporosis pathobiology. To achieve this goal, the overall focus of the CORT is to define the cellular and molecular mechanisms of action of currently-used osteoporosis anabolic agents in humans. A highly-collaborative, multi-disciplinary, international network of investigators based at several Harvard Medical School-based institutions and Imperial College London have come together to tackle this challenge. In Project 1, investigators will define the effects of romosozumab and teriparatide on skeletal stem cells including osteoblast progenitors using flow cytometry, single cell RNA sequencing, and histopathology. Studies will be performed using samples from patients receiving anabolic therapy and in complementary genetically-modified mouse models where lineage tracing and single cell RNA sequencing can be combined. In Project 2, investigators will define the effects of romosozumab and teriparatide on osteocytes. Based on preliminary data, osteocytes can directly regulate bone matrix formation and remodeling, leading to the exciting hypothesis, tested here in human and mouse samples that anabolic agents impact cortical bone via direct effects on osteocytic perilacunar remodeling. Projects 1 and 2 will be supported by a highly innovative Bioinformatics Core that will incorporate cross-species transcriptomics datasets with available human and mouse genetics in order to develop novel hypotheses, also tested here, regarding genes and gene network that mediate bone anabolic responses. CORT efforts will be further enhanced by the complementary experience of investigators in osteoporosis clinical research, bone biomechanics, bone stem cell biology, osteocyte biology, bone marrow microenvironment investigation, statistical genetics, osteoporosis epidemiology, and genetic origins of bone disease.

项目总结 – 总体 骨质疏松症是我们人口老龄化的一个主要问题，而骨质疏松症的药物治疗。 过去 20 年来取得了长足的进步，能够真正降低骨折风险的治疗方法 骨合成代谢疗法（甲状旁腺激素受体激动剂）仍然难以实现年轻水平。 特立帕肽/阿巴洛帕肽和抗硬化素抗体 romosozumab）是 我们针对这种常见、昂贵、严重且使人衰弱的疾病的治疗装备。 优化刺激骨形成的能力，治愈许多患有严重疾病的骨质疏松症患者 值得注意的是，我们目前使用的药物的合成代谢功效会随着时间的推移而减弱，具体情况未知。 CORT 的目标是阐明骨质疏松症合成代谢疗法的作用机制，并 理解他们为什么停止工作 这样做，CORT 将加速知识转化以改进。 我们对骨质疏松症病理学的理解 为了实现这一目标，CORT 的总体重点是 定义目前使用的骨质疏松合成代谢药物的细胞和分子作用机制 一个高度协作、多学科、国际研究人员网络，以多个机构为基础。 哈佛医学院的机构和伦敦帝国理工学院联手解决这个问题 在项目 1 中，研究人员将确定 romosozumab 和特立帕肽对骨骼干的影响。 使用流式细胞术、单细胞 RNA 测序和组织病理学对包括成骨细胞祖细胞在内的细胞进行分析。 研究将使用来自接受合成代谢治疗的患者的样本进行，并补充 可以将谱系追踪和单细胞 RNA 测序结合起来的转基因小鼠模型。 项目 2 中，研究人员将确定 romosozumab 和特立帕肽对骨细胞的影响。 初步数据显示，骨细胞可以直接调节骨基质的形成和重塑，从而导致令人兴奋的结果 假设，在人类和小鼠样本中进行了测试，合成代谢药物通过直接影响皮质骨 项目 1 和 2 将得到高度创新的支持。 生物信息学核心将把跨物种转录组学数据集与可用的人类和 小鼠遗传学，以开发新的假设，也在这里进行了测试，涉及基因和基因网络 介导骨合成代谢反应的作用将通过互补得到进一步增强。 研究人员在骨质疏松症临床研究、骨生物力学、骨干细胞生物学、 骨细胞生物学、骨髓微环境研究、统计遗传学、骨质疏松症 流行病学和骨病的遗传起源。