Nanoparticle-mediated drug delivery for inflammatory Arthritis

项目摘要 炎症性关节炎(IA)是一种自身免疫性疾病，其特征是慢性侵袭性关节炎和 多器官的全身性损害。IA的主要类型包括痛风、银屑病关节炎(PA)和 类风湿关节炎(RA)。类风湿关节炎的发病机制是基于遗传和获得性的复杂相互作用 调节反应和炎症反应之间的免疫平衡缺陷1。调节性T细胞(Treg) 髓系来源的抑制细胞(MDSCs)是典型的免疫调节剂，缺陷或 这些细胞功能障碍参与了类风湿关节炎的发病。含Sh2的肌醇-5‘-磷酸酶- 1(SHIP1)是一种具有磷酸酶活性的酶，控制PI3K启动的信号转导。我们发现 3-α-氨基胆碱酯(3AC)对SHIP1的时间抑制作用 实验性小鼠关节炎(CIA)的进展及其调控的扩展和维持 需要较长时间的细胞才能预防严重炎症 损害赔偿。在我们的初步研究的基础上，我们假设含有以下成分的NPs会产生时间抑制 SHIP1抑制剂(3AC-NPs)不仅扩大了细胞数量，而且增强了细胞的调节功能。另外， IA注射局部抑制炎症部位SHIP1可缓解关节炎 中情局小鼠的症状。通过与Rhode的合作，当前项目的主要目标 岛屿学院和罗德岛医院正在开发一种潜在的关节炎治疗策略 炎症使用SHIP1抑制剂和纳米粒(NPs)。通过这次合作，我们的目标是 制备3AC-NPs并检测其在RA小鼠模型中的抗炎作用 对本科生进行最先进的药物输送和疾病治疗方法的培训。我们预计 注射3AC-NPs可减少滑膜组织的炎症反应。 我们的长期目标是开发治疗炎症性疾病的新策略，以及 为本科生在医学、生物医学工程和制药方面的职业做好准备 工业。

Project Summary Inflammatory Arthritis (IA) is an autoimmune disease characterized by chronic erosive arthritis and systemic lesions of multiple organs. The major types of IA include Gout, Psoriatic arthritis (PA), and Rheumatoid Arthritis (RA). RA pathogenesis is based on complex mutual effects of genetic an acquired defects of immune balance between regulatory and inflammatory responses1. Regulatory T cells (Treg) and Myeloid-derived suppressor cells (MDSCs) are typical immune-regulators, and defects or malfunction of these cells contributes to the pathogenesis of RA. SH2-containing inositol-5'-phosphatase- 1 (SHIP1) is an enzyme with phosphatase activity, which controls PI3K initiated signaling. We found that temporal inhibition of SHIP1 by 3-α-Aminocholestane (3AC) would suppress the initiation and progression of experimental mouse arthritis (CIA), and the expansion and maintenance of regulatory cells for an extended period of time would be required for the prevention of severe inflammatory damages. Based on our preliminary studies, we hypothesize that temporal inhibition by NPs containing SHIP1 inhibitor (3AC-NPs) not only expand cell number, but also enhance regulatory cell function. Also, regional suppression of SHIP1 in inflammation sites through IA injection could relieve the arthritic symptom in CIA mice. The primary objective of the current project through a collaboration with Rhode Island College and Rhode Island Hospital is to develop a potential therapeutic strategy for arthritic inflammation using SHIP1 inhibitor and Nanoparticles (NPs). Through this collaboration we aim to generate 3AC-NPs and to examine the anti-inflammatory functions in RA mouse model as well as train undergraduates in state-of-the-art methods of drug delivery and disease treatment. We expect that that the administration of 3AC-NPs results in reduced inflammatory responses at synovial tissues. Our long-term goal is to develop novel strategies for treatment of inflammatory diseases, as well as prepare undergraduates students for careers in medicine, biomedical engineering, and pharmaceutical industry.