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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).