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.

项目摘要 - 总体 骨质疏松症是我们老龄化人口的主要问题。而骨质疏松的药物治疗 在过去的二十年中，已经取得了长足的进步，可以真正降低骨折风险的治疗 年轻水平仍然难以捉摸。骨合成代谢疗法（甲状旁腺马酮受体激动剂 Teriparatide/baloparatide和抗骨蛋白抗体romosozumab）代表了重要组成部分 我们为这种常见，昂贵，严重和使人衰弱的疾病的治疗性武器库。没有一个 优化刺激骨形成的能力，许多严重疾病患者的骨质疏松症治愈 无法实现。值得注意的是，随着时间的流逝，我们当前使用的代理的合成代谢效率会逐渐减弱 原因。 Cort的目的是阐明骨质疏松症合成代谢疗法的作用机理，并阐明 了解为什么他们停止工作。这样，Cort将加速知识的翻译以改进 我们对骨质疏松病病理学的理解。为了实现这一目标，科特的总体重点是 定义当前使用的骨质疏松剂合成代谢剂的作用的细胞和分子机制 人类。一个高度学科的，多学科的国际调查人员网络，该网络位于几个 哈佛医学院的机构和伦敦帝国学院已经聚集在一起解决这个问题 挑战。在项目1中，研究人员将定义romosozumab和teriparatide对骨骼茎的影响 使用流式细胞术，单细胞RNA测序和组织病理学，包括成骨细胞祖细胞在内。 将使用接受合成代谢疗法的患者的样本进行研究 可以组合谱系跟踪和单细胞RNA测序的遗传修饰的小鼠模型。在 项目2，研究人员将定义romosozumab和teriparatide对骨细胞的影响。基于 初步数据，骨细胞可以直接调节骨基质形成和重塑，导致令人兴奋的 假设在这里在人类和小鼠样品中检验，合成代谢药物通过直接影响皮质骨 对骨细胞细胞重塑的影响。项目1和2将得到高度创新的支持 生物信息学核心将将跨物种转录组学数据集与可用人类和 小鼠仿制药为了开发有关基因和基因网络的新型假设，也在此处进行了测试 介导骨合成代谢反应。完工将进一步加强Cort的努力 研究人员在骨质疏松症临床研究，骨生物力学，骨干细胞生物学的经验， 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。