Sustained Release Relaxin-2 for the Treatment of Frozen Shoulder

缓释松弛素2治疗肩周炎

• 批准号: 10669219
• 负责人: MARK W. GRINSTAFF
• 金额: $ 62.53万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669219
• 关键词: Address; Adhesions; Adrenal Cortex Hormones; Adult; Anesthesia procedures; Animals; Ankle; Articular Range of Motion; Binding; Biological Markers; Caring; Cell physiology; Cells; Characteristics; Childbirth; Chondrocytes; Collaborations; Collagen; Contracture; Cryoelectron Microscopy; Cyclic GMP; Data; Deposition; Disease; Down-Regulation; Drug Kinetics; Effectiveness; Encapsulated; Engineering; Experimental Designs; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Formulation; Freezing; G-Protein-Coupled Receptors; Gene Expression; Glucocorticoid Receptor; Hip region structure; Histologic; Hormones; Human; Immobilization; In Vitro; Individual; Inflammation; Injections; Intra-Articular Injections; Joint structure of shoulder region; Joints; Kinetics; Knee; Ligaments; Ligands; Manuscripts; Matrix Metalloproteinases; Measures; Medical; Modeling; Molecular; Molecular Weight; Myofibroblast; Nerve; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; PTGS2 gene; Pain; Particle Size; Pathway interactions; Patients; Pelvis; Peptides; Phenotype; Physical therapy; Polymers; Population; Pregnant Women; Preparation; Prevalence; Procedures; Property; Proteins; Publishing; Regulation; Relaxin; Risk; Serum; Shoulder; Signal Induction; Signal Pathway; Signal Transduction; Small Interfering RNA; Structure; Symphysis pubis structure; Symptoms; Synovial Fluid; Testing; Therapeutic; Time; Tissues; Trauma; United States; Uterus; Variant; Western Blotting; Wrist; biocompatible polymer; biodegradable polymer; cartilaginous; crystallinity; cyclooxygenase 1; cytotoxicity; diabetic; experimental study; improved; in vivo; in vivo Model; innovation; joint function; joint stiffness; knock-down; member; novel; novel therapeutics; optimal treatments; particle; peptide hormone; pharmacologic; receptor; restorative treatment; small molecule; targeted treatment; transcriptome sequencing

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.

项目摘要/摘要 该提案描述了对肩关节纤维化的创新和恢复性治疗，也称为冷冻 肩膀。在美国的1500万个人中，患有肩关节纤维化的人，超过1.6 百万每年寻求医疗服务。当前的治疗选择，包括关节内皮质类固醇注射， 非甾体类抗炎药（NSAID）和神经阻滞剂仅提供边际和临时救济 患者症状的出现，无法解决疾病的根本原因 - 纤维化的积累 胶原组织。物理治疗是主要治疗选择，但延长且次优。外科 干预措施在严重的情况下使用，但这些程序充满并发症，可以进一步 加重纤维化。我们建议将人类松弛素2（RLX）用作一种新型疗法 肩部节肢动物。 RLX是一种内源性的6 kDa胡椒马，主要有助于软化 通过细胞外基质重塑之前，耻骨联合和骨盆韧带。重新利用这个 治疗关节纤维化的抗纤维化胡椒代表了该疾病的首个蛋白质疗法。 具体而言，我们描述了关节空间中RLX的详细行动机理研究 从新颖和良好的封装和持续的RLX递送。 生物相容性和可生物降解的聚合物。提出的实验将定义分子和 关节空间中RLX信号的结构基础，并将使用体内肩关节合同 固定模型测试RLX通过抑制TGF-β1降低关节纤维化的假设 通过NO-SGC-CGMP途径传导，从而降低关节刚度并增加肩膀 运动范围（ROM）。此外，我们假设RLX从单个关节内持续释放 注射RLX负载的聚合物微粒将减轻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，特征良好的材料和严格的材料 建立了实验设计，并建立了基本的跨学科合作和专业知识 解决这些假设。该五年提案的具体目的如下。 AIM 1定义 RLX结合其接收器RXFP1的分子机制，为基于结构的框架提供了一个框架 RLX的优化。 AIM 2确定RLX负载可生物降解的材料特性和 生物相容性的聚合微粒微粒，包括RLX释放动力学和颗粒降解。 AIM 3评估 使用AIM 2中确定的最佳RLX的微粒公式的药代动力学和效率 已建立的体内肩部缔合模型。