Sustained Release Relaxin-2 for the Treatment of Frozen Shoulder
缓释松弛素2治疗肩周炎
基本信息
- 批准号:10669219
- 负责人:
- 金额:$ 62.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAdhesionsAdrenal Cortex HormonesAdultAnesthesia proceduresAnimalsAnkleArticular Range of MotionBindingBiological MarkersCaringCell physiologyCellsCharacteristicsChildbirthChondrocytesCollaborationsCollagenContractureCryoelectron MicroscopyCyclic GMPDataDepositionDiseaseDown-RegulationDrug KineticsEffectivenessEncapsulatedEngineeringExperimental DesignsExtracellular MatrixExtracellular Matrix ProteinsFibroblastsFibrosisFormulationFreezingG-Protein-Coupled ReceptorsGene ExpressionGlucocorticoid ReceptorHip region structureHistologicHormonesHumanImmobilizationIn VitroIndividualInflammationInjectionsIntra-Articular InjectionsJoint structure of shoulder regionJointsKineticsKneeLigamentsLigandsManuscriptsMatrix MetalloproteinasesMeasuresMedicalModelingMolecularMolecular WeightMyofibroblastNerveNon-Steroidal Anti-Inflammatory AgentsOperative Surgical ProceduresPTGS2 genePainParticle SizePathway interactionsPatientsPelvisPeptidesPhenotypePhysical therapyPolymersPopulationPregnant WomenPreparationPrevalenceProceduresPropertyProteinsPublishingRegulationRelaxinRiskSerumShoulderSignal InductionSignal PathwaySignal TransductionSmall Interfering RNAStructureSymphysis pubis structureSymptomsSynovial FluidTestingTherapeuticTimeTissuesTraumaUnited StatesUterusVariantWestern BlottingWristbiocompatible polymerbiodegradable polymercartilaginouscrystallinitycyclooxygenase 1cytotoxicitydiabeticexperimental studyimprovedin vivoin vivo Modelinnovationjoint functionjoint stiffnessknock-downmembernovelnovel therapeuticsoptimal treatmentsparticlepeptide hormonepharmacologicreceptorrestorative treatmentsmall moleculetargeted treatmenttranscriptome sequencing
项目摘要
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.
项目总结/摘要
该提案描述了一种创新的和恢复性的治疗肩关节纤维化,也被称为冷冻
肩膀在美国患有肩关节纤维化的1500万人中,超过1.6
每年有100万人寻求医疗服务。目前的治疗选择,包括关节内皮质类固醇注射,
非甾体抗炎药(NSAID)和神经阻滞剂只能提供边缘和暂时的缓解
的患者症状,并没有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的治疗选择,但它是长期的和次优的。手术
在严重的情况下使用干预措施,但这些程序充满了并发症,并可能进一步
加重纤维化。我们建议使用人松弛素-2(RLX)作为治疗以下疾病的新疗法:
肩关节纤维化RLX是一种内源性6-kDa肽激素,主要有助于软化
耻骨联合和骨盆韧带分娩前通过细胞外基质重塑。重新利用这个
用于治疗关节纤维化的抗纤维化肽代表了用于这种疾病的第一种蛋白质疗法。
具体而言,我们描述了RLX在关节间隙中的详细作用机制研究,
本发明公开了一种从由新的和良好建立的两种制备的微粒包封和持续递送RLX的方法,
生物相容性和可生物降解的聚合物。拟议的实验将确定分子和
RLX信号在关节间隙的结构基础,并将使用体内肩关节挛缩
制动模型,以检验RLX通过抑制TGF-β1减少关节纤维化的假设
通过NO-sGC-cGMP途径进行信号传导,从而降低关节僵硬并增加肩部
活动范围(ROM)。此外,我们假设从单个关节内持续释放RLX
注射载有RLX的聚合物微粒将减轻关节纤维化的症状和病因。
重要的是,初步数据支持拟议的研究,良好表征的材料和严格的
实验设计已经确立,重要的跨学科合作和专业知识已经到位
来解决这些假设。这一五年建议的具体目标如下。目标1定义了
RLX结合其受体RXFP 1的分子机制,为基于结构的
优化RLX。目的2确定负载RLX的可生物降解和生物降解材料的材料性能特征,
生物相容性聚合物微粒,包括RLX释放动力学和颗粒降解。目标3评估
目的2中确定的最佳RLX负载微粒制剂的药代动力学和功效,
建立了肩关节挛缩的体内模型。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
MARK W. GRINSTAFF其他文献
MARK W. GRINSTAFF的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('MARK W. GRINSTAFF', 18)}}的其他基金
R21: A novel antibody-drug conjugate for treatment of squamous cell lung carcinoma
R21:一种用于治疗鳞状细胞肺癌的新型抗体药物偶联物
- 批准号:
10510002 - 财政年份:2022
- 资助金额:
$ 62.53万 - 项目类别:
R21: A novel antibody-drug conjugate for treatment of squamous cell lung carcinoma
R21:一种用于治疗鳞状细胞肺癌的新型抗体药物偶联物
- 批准号:
10671669 - 财政年份:2022
- 资助金额:
$ 62.53万 - 项目类别:
The Conundrum of Absentee Receptors: Efficacy Potentiation Through Drug-Receptor Modulation
缺失受体的难题:通过药物受体调节增强功效
- 批准号:
10708018 - 财政年份:2022
- 资助金额:
$ 62.53万 - 项目类别:
Sustained Release Relaxin-2 for the Treatment of Frozen Shoulder
缓释松弛素2治疗肩周炎
- 批准号:
10443323 - 财政年份:2022
- 资助金额:
$ 62.53万 - 项目类别:
A novel approach for reversal of autophagic defects using lysosome-targeted nanoparticles
使用溶酶体靶向纳米颗粒逆转自噬缺陷的新方法
- 批准号:
9914192 - 财政年份:2019
- 资助金额:
$ 62.53万 - 项目类别:
A novel approach for reversal of autophagic defects using lysosome-targeted nanoparticles
使用溶酶体靶向纳米颗粒逆转自噬缺陷的新方法
- 批准号:
9752911 - 财政年份:2019
- 资助金额:
$ 62.53万 - 项目类别:
R21: Acidic Nanoparticles for Restoration of Autophagy in Age-associated NAFLD
R21:酸性纳米颗粒用于恢复年龄相关性 NAFLD 中的自噬
- 批准号:
9902306 - 财政年份:2019
- 资助金额:
$ 62.53万 - 项目类别:
Dissolvable Hydrogel Dressing for the Treatment of Burns
用于治疗烧伤的可溶性水凝胶敷料
- 批准号:
9010534 - 财政年份:2016
- 资助金额:
$ 62.53万 - 项目类别:
Synthesis, Characterization, and Evaluation of Polymeric Tissue Lubricants
聚合物组织润滑剂的合成、表征和评估
- 批准号:
8886944 - 财政年份:2014
- 资助金额:
$ 62.53万 - 项目类别:
相似海外基金
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y004841/1 - 财政年份:2024
- 资助金额:
$ 62.53万 - 项目类别:
Research Grant
Defining a role for non-canonical mTORC1 activity at focal adhesions
定义非典型 mTORC1 活性在粘着斑中的作用
- 批准号:
BB/Y001427/1 - 财政年份:2024
- 资助金额:
$ 62.53万 - 项目类别:
Research Grant
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y005414/1 - 财政年份:2024
- 资助金额:
$ 62.53万 - 项目类别:
Research Grant
Development of a single-use, ready-to-use, sterile, dual chamber, dual syringe sprayable hydrogel to prevent postsurgical cardiac adhesions.
开发一次性、即用型、无菌、双室、双注射器可喷雾水凝胶,以防止术后心脏粘连。
- 批准号:
10669829 - 财政年份:2023
- 资助金额:
$ 62.53万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10587090 - 财政年份:2023
- 资助金额:
$ 62.53万 - 项目类别:
Improving Maternal Outcomes of Cesarean Delivery with the Prevention of Postoperative Adhesions
通过预防术后粘连改善剖宫产的产妇结局
- 批准号:
10821599 - 财政年份:2023
- 资助金额:
$ 62.53万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10841832 - 财政年份:2023
- 资助金额:
$ 62.53万 - 项目类别:
Prevention of Intraabdominal Adhesions via Release of Novel Anti-Inflammatory from Surface Eroding Polymer Solid Barrier
通过从表面侵蚀聚合物固体屏障中释放新型抗炎剂来预防腹内粘连
- 批准号:
10532480 - 财政年份:2022
- 资助金额:
$ 62.53万 - 项目类别:
I-Corps: A Sprayable Tissue-Binding Hydrogel to Prevent Postsurgical Cardiac Adhesions
I-Corps:一种可喷雾的组织结合水凝胶,可防止术后心脏粘连
- 批准号:
10741261 - 财政年份:2022
- 资助金额:
$ 62.53万 - 项目类别:
Sprayable Polymer Blends for Prevention of Site Specific Surgical Adhesions
用于预防特定部位手术粘连的可喷涂聚合物共混物
- 批准号:
10674894 - 财政年份:2022
- 资助金额:
$ 62.53万 - 项目类别: