BLRD Research Career Scientist Award Application.

摘要： 骨关节炎（OA），通常被称为关节炎，引起关节疼痛，是最常见的慢性 退伍军人的情况。事实上，退伍军人的情况比非退伍军人更糟; 每四名退伍军人中就有一人患有严重的关节炎，40岁以上的人患关节炎的可能性是40岁以上的人的两倍。 回到平民生活后患上关节炎。骨关节炎的症状，疼痛，是就医的关键原因 然而，没有有效的方法来缓解OA引起的疼痛。 尽管慢性OA的严重疼痛对生活质量和医疗保健有重大负面影响， 管理，我们只知之甚少的起源疼痛的OA，分子机制驱动的 病理学，以及有效治疗OA的方法。许多病例最终需要使用 假体价格昂贵，功能寿命有限（~10年），可进行二次置换 必要这些因素增加了治疗的总成本和相关发病率的风险。 值得注意的是，解决这种情况的外科手术通常不会导致无痛治愈。 我们的中心假设是Flt 1（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）和中枢神经胶质激活的可塑性的关节疼痛传递驱动器; Flk 1 （血管内皮生长因子受体-2）主要负责OA期间的软骨退变 因此，通过FDA批准的小分子帕唑帕尼同时抑制Flt 1和Flk 1， 抗癌药物，将作为一个理想的OA疾病修饰药物（OADMD），立即减少关节炎， 疼痛和逐渐软骨再生。我们提出的研究结果将采取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， 和进展的OA，并通过开发一种新的策略，有效和安全地治疗OA和关节疼痛 在我们的临床前OA动物模型中;并且，从长远来看，通过为临床试验提供理论依据来测试 帕唑帕尼治疗OA患者。

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.