Sustained Release Relaxin-2 for the Treatment of Frozen Shoulder

项目摘要/摘要 这份提案描述了一种治疗肩关节纤维化的创新和恢复性治疗方法，也称为冷冻治疗。 肩膀。在美国1500万肩关节纤维化患者中，超过160万人 每年有100万人寻求医疗服务。目前的治疗方案，包括关节内注射皮质类固醇， 非类固醇抗炎药(NSAIDs)和神经阻滞剂只能起到边际和暂时的缓解作用 没有解决疾病的根本原因--纤维化的堆积 胶原组织。物理治疗是一种主要的治疗方法，但时间长，效果不佳。外科手术 在病情严重的情况下可以进行干预，但这些程序充满并发症，可能会进一步 加重纤维化。我们建议使用人松弛素-2(RLX)作为一种新的治疗方法。 肩关节纤维化症。RLX是一种内源性6 kDa的多肽激素，主要帮助软化 耻骨联合和骨盆韧带在分娩前通过细胞外基质重塑。重新调整这一用途 用于治疗关节纤维化的抗纤维化多肽是治疗这种疾病的第一种蛋白质疗法。 具体地说，我们描述了RLX在关节间隙结合的详细作用机制研究 RLX从新型和成熟制备的微球中的包封化和缓释 生物相容性和生物降解性聚合物。拟议中的实验将定义分子和 关节间隙中RLX信号的结构基础，并将使用活体肩关节痉挛 RLX通过抑制转化生长因子-β-1减少关节纤维化假说的固定模型 通过NO-sGC-cGMP途径传递信号，从而降低关节僵硬和增加肩部 运动范围(ROM)。此外，我们假设RLX从单个关节内持续释放 注射负载RLX的聚合物微粒将缓解关节纤维化的症状和原因。 重要的是，初步数据支持拟议的研究，良好的表征材料和严格的 建立了实验设计，并建立了必要的跨学科协作和专业知识 来解决这些假说。这一五年计划的具体目标如下。目标1定义了 RLX与其受体RXFP1结合的分子机制，为基于结构的 RLX的优化。目的2确定负载RLX的可生物降解材料的材料性能特征 生物相容聚合物微粒，包括RLX释放动力学和微粒降解。AIM 3评估 AIM 2中确定的最佳RLX微粒制剂的药代动力学和有效性 已建立的活体肩关节挛缩症模型。

PROJECT SUMMARY/ABSTRACT This proposal describes an innovative and restorative treatment for shoulder arthrofibrosis, also known as frozen shoulder. Of the 15 million individuals in the United States suffering from shoulder arthrofibrosis, more than 1.6 million seek medical care each year. Current treatment options, including intraarticular corticosteroid injections, non-steroidal anti-inflammatory drugs (NSAIDs), and nerve blockers, provide only marginal and temporary relief of patient symptoms and do not address the underlying cause of the disease – the accumulation of fibrotic collagenous tissue. Physical therapy is a main treatment option but it is prolonged and suboptimal. Surgical interventions are used in severe cases, but these procedures are fraught with complications and can further aggravate the fibrosis. We propose the use of human relaxin-2 (RLX) as a novel therapeutic for the treatment of shoulder arthrofibrosis. RLX is an endogenous 6-kDa peptide hormone that primarily aids in softening of the pubic symphysis and pelvic ligaments prior to childbirth via extracellular matrix remodeling. Repurposing this antifibrotic peptide to treat arthrofibrosis represents a first-of-its-kind protein therapy for this disease. Specifically, we describe detailed mechanism-of-action studies for RLX in the joint space combined with encapsulation and sustained delivery of RLX from microparticles prepared from both novel and well-established biocompatible and biodegradable polymers. The proposed experiments will define the molecular and structural basis for RLX signaling in the joint space and will use an in vivo shoulder joint contracture immobilization model to test the hypothesis that RLX reduces arthrofibrosis by inhibiting TGF-β1 signaling via the NO-sGC-cGMP pathway, thereby decreasing joint stiffness and increasing shoulder range of motion (ROM). Further, we hypothesize that sustained release of RLX from a single intraarticular injection of RLX-loaded polymeric microparticles will alleviate both the symptoms and causes of arthrofibrosis. Importantly, preliminary data support the proposed studies, well-characterized materials and rigorous experimental designs are established, and essential cross-disciplinary collaborations and expertise are in place to address the hypotheses. The specific aims of this five-year proposal are as follows. Aim 1 defines the molecular mechanism of by which RLX binds its receptor, RXFP1, providing a framework for structure-based optimization of RLX. Aim 2 determines the material property characteristics of RLX-loaded biodegradable and biocompatible polymeric microparticles, including RLX release kinetics and particle degradation. Aim 3 assesses the pharmacokinetics and efficacy of the optimal RLX-loaded microparticle formulation identified in Aim 2 using an established in vivo shoulder contracture model.