BLRD Research Career Scientist Award Application.

BLRD 研究职业科学家奖申请。

• 批准号: 10366566
• 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
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366566
• 关键词: Achievement; Address; Adverse drug effect; Adverse effects; Affect; Afferent Neurons; Age; Animal Model; Animals; Antibodies; Antibody Therapy; Antineoplastic Agents; Area; Arthralgia; Arthritis; Automobile Driving; Award; Behavioral; Cartilage; Cells; Chronic; Clinical; Clinical Trials; Complex; Data; Degenerative polyarthritis; Disease; Disease Progression; Drug Formulations; Economic Burden; FDA approved; Genes; Goals; Hyaluronic Acid; Individual; Injections; Injury; Joints; KDR gene; Knee Osteoarthritis; Knee joint; Life; Ligands; Low Back Pain; Medical; Medical Assistance; Military Personnel; Modeling; Molecular; Morbidity - disease rate; Mus; Musculoskeletal Pain; Nerve Growth Factors; Nociception; Operative Surgical Procedures; Opiate Addiction; Opioid; Pain; Pain Origin; Pain-Free; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase III Clinical Trials; Prosthesis; Publications; Quality of life; Replacement Arthroplasty; Reporting; Research; Rhubarb food; Role; Scientist; Severities; Source; Spinal Ganglia; Symptoms; Synovial Membrane; Technology; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Treatment Cost; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Veterans; Work; addiction; base; bevacizumab; blood vessel development; bone; career; cartilage degradation; cartilage regeneration; chronic pain; cost; disability; drug efficacy; effective therapy; factor J; glial activation; health management; inflammatory pain; innovation; insurance claims; novel strategies; osteoarthritis pain; pain reduction; pain relief; pain sensation; pain symptom; personalized medicine; pre-clinical; prevent; receptor; small molecule; social; tissue regeneration; transmission process; treatment risk; treatment strategy

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，引起疼痛的关节，是最常见的慢性 退伍军人的条件。实际上，退伍军人中的病情比非退伍军人要差得多。之一 每四名退伍军人生活具有严重的关节炎状况，40岁以上的个人的可能性是 恢复平民生活后发展关节炎。骨关节炎症状，疼痛是寻求医疗的关键原因 援助，但是没有有效的方法可以缓解OA引起的疼痛。 尽管慢性OA严重疼痛对生活质量和医疗保健产生了重大负面影响 管理层，我们只了解OA疼痛的起源，这是驱动的分子机制 病理，以及有效治愈OA的方法。许多情况最终需要用 假体昂贵，而假肢的功能有限（约10年）可以进行第二次替换 必要的。这些因素增加了治疗的总体成本和相关发病率的风险。 值得注意的是，解决该疾病的手术程序通常不会导致无痛治疗。 我们的中心假设是FLT1的激活（血管内皮生长因子受体1）是主要的 通过外周（感觉神经元）和中央神经胶质激活的可塑性，关节疼痛传播的驱动器； FLK1 （血管内皮生长因子受体2）主要负责OA期间软骨变性 因此，通过Pazopanib（FDA批准的小分子）同时抑制FLT1和FLK1 抗癌药将充当理想的OA疾病改良药物（OADMD），立即减少关节 疼痛和逐渐发生软骨的再生。我们拟议的研究的发现将采用OA领域 研究巨大的一步：在短期内，通过提高我们对原因的机械理解 和OA的进展，并通过制定一种新颖的策略来有效，安全地治疗OA和关节疼痛 在我们的临床前OA动物模型中；从长远来看，通过提供临床试验的基本原理进行测试 pazopanib治疗OA患者。