Osteoarthritis and Knee Joint Pain

骨关节炎和膝关节疼痛

基本信息

批准号：
10427174
负责人：
Hee-Jeong Im Sampen
金额：
--
依托单位：
JESSE BROWN VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-10-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10427174
关键词：
Address Affect Afferent Neurons Age Analgesics Animal Model Animals Antineoplastic Agents Area Arthralgia Arthritis Astrocytes Automobile Driving Behavioral Cells Chronic Clinical Clinical Trials Degenerative polyarthritis Disease Economic Burden Family Frequencies Genes Genomics Goals Health system Human Hyaluronic Acid Incidence Individual Injury Intra-Articular Injections Joints KDR gene Knee joint Knowledge Letters Life Ligands Macular degeneration Malignant Neoplasms Medial Medical Medical Assistance Military Personnel Modeling Molecular Morbidity - disease rate Mus Neuronal Plasticity Neurons Nociception Operative Surgical Procedures PGF gene Pain Pain Origin Pain-Free Pathologic Pathologic Neovascularization Pathology Pathway interactions Patients Peripheral Pharmaceutical Preparations Pharmacology Play Population Prosthesis Public Health Quality of life Receptor Protein-Tyrosine Kinases Replacement Arthroplasty Reporting Research Role Safety Sensory Signal Transduction Spinal Spinal Cord Symptoms Synaptic Transmission Technology Testing Therapeutic Effect Time Tissue Sample Tissues Trauma Treatment Cost United States Food and Drug Administration VEGFA gene Vascular Endothelial Growth Factor B Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Veterans Virus Work ZD-6474 blood vessel development cartilage degradation cartilage regeneration central pain controlled release cost crosslink disability drug efficacy drug testing gender difference glial activation health management industry partner inhibitor novel strategies osteoarthritis pain pain reduction pre-clinical prevent receptor response small molecule small molecule inhibitor tissue regeneration transmission process treatment risk

项目摘要

ABSTRACT: Osteoarthritis (OA), commonly referred as arthritis, causing painful joints, is among the most common chronic conditions among veterans. Indeed, the condition is much worse among veterans than non-veterans; one of every four veterans lives with a serious arthritic condition and individuals over age 40 are twice as likely to develop arthritis after returning to civilian life. Osteoarthritic symptom, pain, is the key reason to seek medical assistance, yet there is no effective way to relieve OA-induced pain. Despite the major negative impact that severe pain in chronic OA has on quality of life and health care management, we only poorly understand origins of pain in OA, the molecular mechanisms driving the pathology, and the way to effectively cure OA. Many cases eventually require joint replacement with a prosthesis which is costly, and the limited functional life of prostheses (~10 y) can make a second replacement necessary. These factors increase both the overall cost of treatment and the risk for associated morbidity. Significantly, surgical procedures to address the condition typically do not result in a pain-free cure. Our central hypothesis is that activation of Flt1 (vascular endothelial growth factor receptor-1) is the major driver of joint pain transmission by plasticity of peripheral (sensory neurons) and central glial activation; Flk1 (vascular endothelial growth factor receptor-2) is primarily responsible for cartilage degeneration during the OA progression, thus, simultaneous inhibition of Flt1 and Flk1 by pazopanib, an FDA-approved small molecule anti-cancer drug, will act as an ideal OA disease-modifying drug (OADMD) with immediate reduction of joint pain and gradually cartilage regeneration. The findings of our proposed research will take the field of OA research a giant step forward: in the short term, by increasing our mechanistic understanding of the causes and progression of OA, and by developing a novel strategy for treating OA and joint pain effectively and safely in our pre-clinical OA animal model; and, in the longer term, by providing a rationale for clinical trials to test pazopanib to treat OA patients.

抽象的：骨关节炎 (OA)，通常称为关节炎，会导致关节疼痛，是最常见的慢性疾病之一退伍军人之间的状况。事实上，退伍军人的情况比非退伍军人要糟糕得多。之一每四名退伍军人中就有一名患有严重的关节炎，而 40 岁以上的退伍军人患严重关节炎的可能性是其两倍返回平民生活后患关节炎。骨关节炎症状、疼痛是就医的主要原因目前尚无有效的方法来缓解 OA 引起的疼痛。尽管慢性骨关节炎的剧烈疼痛对生活质量和医疗保健产生重大负面影响在管理方面，我们对 OA 疼痛的起源、驱动疼痛的分子机制知之甚少。病理学，以及有效治疗OA的方法。许多病例最终需要关节置换术假体价格昂贵，而且假体的功能寿命有限（~10年）可以进行第二次更换必要的。这些因素增加了治疗的总体成本和相关发病的风险。值得注意的是，针对这种情况的外科手术通常不会带来无痛治愈。我们的中心假设是 Flt1（血管内皮生长因子受体-1）的激活是主要的通过外周（感觉神经元）的可塑性和中枢神经胶质的激活驱动关节疼痛传递；弗尔克1 （血管内皮生长因子受体-2）主要负责 OA 期间的软骨退化因此，帕唑帕尼（FDA 批准的小分子）同时抑制 Flt1 和 Flk1 抗癌药物，将作为理想的 OA 疾病缓解药物 (OADMD)，可立即减少关节损伤疼痛并逐渐软骨再生。我们提议的研究结果将涉及 OA 领域研究向前迈出了一大步：在短期内，通过增加我们对原因的机械理解和进展，并开发一种有效、安全地治疗 OA 和关节疼痛的新策略在我们的临床前 OA 动物模型中；从长远来看，通过为临床试验提供理由来测试帕唑帕尼用于治疗 OA 患者。