Treatment of glucocorticoid-induced osteonecrosis with nano-fullerenes

纳米富勒烯治疗糖皮质激素引起的骨坏死

基本信息

批准号：
8284835
负责人：
Quanjun Cui
金额：
$ 17.33万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8284835
关键词：
Affect Animal Model Antioxidants Apoptosis Attention Autoimmune Diseases Award Biochemistry Biocompatible Materials Biology Blood Blood Flow Cytometry Bone Marrow Bone necrosis Cell Culture Techniques Cell membrane Clinical Trials Complement Complex Data Development Dexamethasone Disease Early Diagnosis Effectiveness Etiology Femur Flow Cytometry Fullerenes Glucocorticoids Glutathione Goals Head Histology Histopathology In Vitro Inflammatory Injection of therapeutic agent Intervention Knowledge Label Lead Life Marrow Measures Methodology Methylprednisolone Modeling Operative Surgical Procedures Orthopedics Oryctolagus cuniculus Outcome Oxidation-Reduction Oxidative Stress Pathogenesis Patients Pharmaceutical Preparations Pharmacologic Substance Play Prevention Preventive Principal Investigator Property Protocols documentation Radioactive Reactive Oxygen Species Research Research Personnel Role Scheme Scientist Solubility Spinal Stromal Cells Surgeon Suspension substance Suspensions Therapeutic Time Venous Western Blotting Yang aqueous base biological preparation bone experience fullerene C60 in vivo innovation intervertebral disk degeneration lipid biosynthesis nano nanoparticle novel novel therapeutics particle single photon emission computed tomography uptake young adult

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this project is to establish an innovative therapeutic approach toward glucocorticoid-induced osteonecrosis of the femoral head (ONFH), using nano-fullerenes which function as outstanding reactive oxygen species (ROS) scavengers. Glucocorticoid administration for treatment of various inflammatory and autoimmune diseases is the most common non-traumatic cause of ONFH. ONFH is a debilitating disease affecting young adults from the third decade of life. Consequently most patients often need multiple increasingly difficult surgeries over the course of their lifetime. Successful treatment of ONFH still remains a big challenge to both scientists and clinicians, due to the difficulties in its early diagnose, the complexity in its etiology and the limited knowledgein its pathogenesis. The hypothesis is that nano-fullerenes might be very effective in treatment of ONFH, and a polyhydroxylated fullerene fullerol with better solubility might elicit a greater activity than the pristine C60. The following specific aims are included: 1. To determine the antagonizing activity of nano-fullerenes against dexamethasone (DEX)- induced adipogenesis and apoptosis in rabbit bone marrow stromal cells in vitro. 2. To evaluate in vivo preventive effects of nano-fullerenes on the development of osteonecrosis of the femoral head (ONFH) in a rabbit model. Aqueous nanoparticle suspension will be prepared from the pristine C60 and fullerol. These two nano-fullerenes and glutathione will be administered and their effectiveness in prevention and treatment of ONFH will be determined in vitro in cell culture and in vivo in an animal model. Various experimental approaches such as histology, real-time PCR, western blot, flow cytometry, blood biochemistry, femur histopathology and single photon emission computed tomography (SPECT) will be employed. It is expected that all three antioxidants can inhibit ONFH development but the activity of fullerol is the strongest. These outcomes would support an innovative concept that nano-fullerenes can effectively treat glucocorticoid-induced ONFH. The study will provide scientific basis for a new therapeutic strategy and lead to novel development of pharmaceutical drugs for ONFH treatment. PUBLIC HEALTH RELEVANCE: Nano-fullerenes will be prepared and assessed for their in vitro and in vivo preventive effects on osteonecrosis of the femoral head (ONFH) induced by glucocorticoid. ONFH is a debilitating disease which begins to affect young adults from the third decade of life. The information obtained from the project will further our knowledge and constitute a major step forward in the field of its pharmacological intervention.

描述（由申请人提供）：该项目的长期目标是使用纳米富勒烯作为出色的活性氧（ROS）清除剂，建立一种针对糖皮质激素引起的股骨头坏死（ONFH）的创新治疗方法。用于治疗各种炎症和自身免疫性疾病的糖皮质激素给药是 ONFH 最常见的非创伤性原因。 ONFH 是一种使人衰弱的疾病，影响 30 岁以上的年轻人。因此，大多数患者在一生中往往需要进行多次难度越来越大的手术。由于ONFH早期诊断困难、病因复杂、发病机制了解有限，成功治疗ONFH仍然是科学家和临床医生面临的一大挑战。假设纳米富勒烯可能对治疗 ONFH 非常有效，并且具有更好溶解度的多羟基富勒烯富勒醇可能会比原始 C60 产生更大的活性。具体目标如下： 1. 确定纳米富勒烯对地塞米松（DEX）诱导的体外兔骨髓基质细胞脂肪生成和细胞凋亡的拮抗活性。 2. 在兔模型中评价纳米富勒烯对股骨头坏死（ONFH）发展的体内预防作用。水性纳米颗粒悬浮液将由原始 C60 和富勒醇制备。将施用这两种纳米富勒烯和谷胱甘肽，并在体外细胞培养物和体内动物模型中确定它们预防和治疗 ONFH 的有效性。将采用各种实验方法，如组织学、实时 PCR、蛋白质印迹、流式细胞术、血液生化、股骨组织病理学和单光子发射计算机断层扫描 (SPECT)。预计所有三种抗氧化剂都能抑制 ONFH 的发展，但富勒醇的活性最强。这些结果将支持纳米富勒烯可以有效治疗糖皮质激素引起的 ONFH 的创新概念。该研究将为新的治疗策略提供科学依据，并导致治疗ONFH药物的新开发。公共健康相关性：将制备纳米富勒烯并评估其对糖皮质激素引起的股骨头坏死 (ONFH) 的体外和体内预防作用。 ONFH 是一种使人衰弱的疾病，从三十岁开始影响年轻人。从该项目中获得的信息将进一步加深我们的认识，并构成其药理干预领域的重要一步。