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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：父授予的目的是研究Notch信号在炎症性骨质疏松症中的作用。我们发现，间充质干/祖细胞中缺口的持续激活限制了其成骨细胞（OB）分化潜力并导致骨质流失，这可以通过Notch抑制剂，DAPT和Thapsigarin [1]预防。我们的发现表明Notch抑制剂可以用作骨合成代谢剂。但是，由于全身分布[2]，缺口抑制剂会严重不良反应，从而限制了它们在骨质疏松症等常见疾病中的使用。这样，使骨头靶向缺口抑制剂减少其全身副作用将是一种非常有吸引力的方法。在这项修订中，我们将组建一个NE跨学科团队，包括一名骨骼生物学家（Xing博士，父母赠款的PI）和化学家（Boeckman博士，修订版的Co-PI；修订顾问），通过使用Bortezomib释放Bortezomib的Bortephopphomib，以设计和合成bortezomib的borte bort bort bort bort，该bort使用bortezomib释放borte bort bort coarbemate carbort carbamate carbamate that carbamate and coarbamib硼替佐酯。提出了两个特殊目标。在AIM 1中，我们将设计和综合靶向骨靶向的硼替佐米结合物，在AIM 2中，我们将检查ob培养物和小鼠骨折愈合中的骨靶向硼替佐米偶联物的生物活性。如果我们取得成功，我们将使用类似的方法来合成骨骼靶向缺口抑制剂，以减少其在治疗炎症性骨质疏松症的治疗中的毒性作用，父母赠款的主要目标，也许是与感染有关的其他骨骼损失。该应用程序还将为这两个DRS提供新的方向。 Xing和Boeckman的实验室：了解泛素 - 蛋白酶体系统在老年人群中骨折修复中的作用，重点是间充质茎/祖细胞（Xing's Lab）；并在其他药物和化合物中使用新型的化学连接器，该化学连接器将打开骨头靶向化学的新策略（Boeckman's Lab）。