Study of osteoblast regulation in TNF-mediated bone loss

TNF介导的骨丢失中成骨细胞调节的研究

• 批准号: 8891736
• 负责人: ROBERT K BOECKMAN
• 金额: $ 7.68万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891736
• 关键词: Adverse effects; Affect; Alkaline Phosphatase; American; Amines; Anabolic Agents; Animal Model; Arthritis; Binding; Biological Assay; Biomechanics; Blood Circulation; Bone Diseases; Bone Marrow; Bone Matrix; Bone Regeneration; Bone Tissue; Bone callus; Bortezomib; CXCR4 gene; Carbamates; Cell physiology; Cells; Chemicals; Chemistry; Clinic; Clinical; Complex; Development; Disease; Dose; Drug Compounding; Drug Targeting; Environment; Esters; FDA approved; Fracture; Fracture Healing; Goals; Growth; Healed; Histology; Homing; Human; Hydrolysis; Immune; In Vitro; Inflammation; Inflammatory; Label; Lead; Malignant Neoplasms; Mediating; Mesenchymal; Messenger RNA; Metastatic Neoplasm to the Bone; Mission; Multiple Myeloma; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Neoplasm Metastasis; Nodule; Osteoblasts; Osteoporosis; Outcome; Pain; Patients; Peptide Hydrolases; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phase; Population; Post-Translational Protein Processing; Process; Proteasome Inhibitor; Proteins; Regulation; Role; Signal Transduction; Site; Spleen; Staining method; Stains; Stem cells; Stromal Cells; System; TNF gene; Technology; Testing; Therapeutic; Thymus Gland; Toxic effect; Ubiquitin; Velcade; Western Blotting; aged; bisphosphonate; bone; bone loss; bone strength; cell motility; chemical synthesis; cost; design; drug candidate; experience; factor A; healing; improved; in vivo; inhibitor/antagonist; medical complication; medical specialties; member; migration; multicatalytic endopeptidase complex; nestin protein; notch protein; novel; novel strategies; novel therapeutic intervention; osteoblast differentiation; osteogenic; parent grant; prevent; public health relevance; repaired; stem; targeted delivery; tibia; tumor; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): The goal of the parent grant is to investigate the role of Notch signaling in inflammatory osteoporosis. We found that persistent activation of Notch in mesenchymal stem/progenitor cells limits their osteoblast (OB) differentiation potential and causes bone loss, which can be prevented by Notch inhibitors, DAPT and Thapsigarin [1]. Our findings suggest that Notch inhibitors could be used as bone anabolic agents. However, Notch inhibitors have severe adverse effects due to systemic distribution [2], limiting their use in common diseases such as osteoporosis. Thus, making bone targeted Notch inhibitors to reduce their systemic side effects will be a very attractive approach. In this revision, we will form a ne interdisciplinary team including a Bone Biologist (Dr. Xing, the PI of the parent grant) and Chemists (Dr. Boeckman, a co-PI of the revision; Dr. Ebetino, consultant of the revision) to design and synthesize bone targeted Bortezomib by conjugating it to a bisphosphonate using a novel carbamate linker that will release Bortezomib from the Bortezomib- bisphosphonate. Two special aims are proposed. In aim 1, we will design and synthesize bone-targeted Bortezomib conjugates and in aim 2, we will examine the bioactivity of bone-targeted Bortezomib conjugates in OB cultures and in mouse fracture healing. If we are successful, we will use a similar approach to synthesize bone targeted Notch inhibitors to reduce their toxic effects in the treatment of inflammatory osteoporosis, a main goal of the parent grant, and perhaps in other bone loss related to inflammation. The application will also lead to new directions for both Drs. Xing and Boeckman's lab: understanding the role of the ubiquitin- proteasome system in bone fracture repair in the aged population with a focus on mesenchymal stem/progenitor cells (Xing's lab); and using a novel chemical linker in other drugs and compounds, which will open a new strategy of bone targeting chemistry (Boeckman's lab).

 描述（由申请人提供）：母基金的目标是研究Notch信号在炎症性骨质疏松症中的作用。我们发现，间充质干细胞/祖细胞中Notch的持续激活限制了其成骨细胞（OB）分化潜力并导致骨丢失，这可以通过Notch抑制剂DAPT和Thapsigarin预防[1]。我们的研究结果表明，Notch抑制剂可用作骨合成代谢剂。然而，Notch抑制剂由于全身分布而具有严重的不良反应[2]，限制了其在常见疾病如骨质疏松症中的使用。因此，制造骨靶向Notch抑制剂以减少其全身副作用将是一种非常有吸引力的方法。在本修订版中，我们将组建一个新的跨学科团队，包括骨生物学家（Xing博士，母基金的PI）和化学家（Boeckman博士，修订版的共同PI; Ebetino博士，修订版的顾问），通过使用新型氨基甲酸酯连接体将其与双膦酸盐结合来设计和合成骨靶向硼替佐米，该连接体将从硼替佐米-双膦酸盐中释放硼替佐米。提出了两个特殊的目标。在目标1中，我们将设计和合成骨靶向硼替佐米缀合物，在目标2中，我们将检查骨靶向硼替佐米缀合物在OB培养物和小鼠骨折愈合中的生物活性。如果我们成功了，我们将使用类似的方法来合成骨靶向Notch抑制剂，以减少其在治疗炎症性骨质疏松症中的毒性作用，这是母基金的主要目标，也可能是其他与炎症相关的骨丢失。Xing博士和Boeckman实验室的应用也将带来新的方向：了解泛素-蛋白酶体系统在老年人群骨折修复中的作用，重点是间充质干细胞/祖细胞（Xing的实验室）;并在其他药物和化合物中使用新型化学接头，这将开辟骨靶向化学的新策略（Boeckman的实验室）。