Injectable Biomaterials to Modulate Protease Activity in Tendinopathy

可注射生物材料调节肌腱病中的蛋白酶活性

• 批准号: 8725054
• 负责人: Johnna S Temenoff
• 金额: $ 29.2万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725054
• 关键词: Aftercare; Athletic; Biocompatible Materials; Cathepsins; Charge; Collagen; Cumulative Trauma Disorders; Cysteine; Cysteine Protease; Degenerative Disorder; Degenerative polyarthritis; Development; Disease; Drug Formulations; Early Intervention; Engineering; Enzymes; Extracellular Matrix; Extracellular Matrix Degradation; Goals; Healed; Heparin; Histology; Hydrogels; Immunohistochemistry; Injectable; Injection of therapeutic agent; Knowledge; Lead; Matrix Metalloproteinases; Mechanics; Mediating; Methodology; Mission; Modeling; Motion; Pain; Pathology; Peptide Hydrolases; Polymers; Property; Protease Inhibitor; Proteins; Public Health; Rattus; Regenerative Medicine; Regulation; Relative (related person); Research; Role; Running; Sampling; Structure; Techniques; Tendinopathy; Tendon structure; Testing; Time; Tissues; Up-Regulation; Western Blotting; Work; Workplace; base; collagenase; controlled release; design; disability; healing; improved; in vivo; inhibitor/antagonist; innovation; intervertebral disk degeneration; post gamma-globulins; prevent; protective effect; public health relevance; repaired; supraspinatus muscle; therapy development

DESCRIPTION (provided by applicant): Tendinopathy is a common tendon disorder resulting from repetitive motion in the workplace or during athletic activity that can cause severe pain and long-term disability. A hallmark of tendinopathy is disruption of extracellular matrix (ECM), particularly collagen, which leads to loss of tissue mechanical properties and function. Although various classes of ECM proteases have been implicated in tissue degeneration in tendinopathy, their relative amounts and the timing of their expression remains unclear. This lack of knowledge has significantly hampered development of treatments to deliver inhibitory agents for these enzymes to reduce pathology progression and improve healing in tendinopathy. Our long-term goal is to develop improved regenerative medicine strategies to aid repair of tendinopathic tissues. The central hypothesis of this proposal is that long-term regulation of protease activity in tendinopathy using injectable biomaterials supporting sustained delivery of a protease inhibitor will result in greater tendon tissue structure and mechanical properties compared with injection of inhibitor without the carrier. Our overall objective will be accomplished by testing our central hypothesis in the following two specific aims: 1) Investigate proteases and inhibitors related to ECM degradation in vivo in a rat supraspinatus tendon overuse model. 2) Evaluate the effects of sustained release of a protease inhibitor on the development of overuse injury in rat supraspinatus tendons. The proposed work is innovative because it employs a well-controlled, injectable carrier to achieve local, sustained release of protease inhibitors to protect against further tissue degeneration in tendinopathy. Results from these studies are expected to have a significant impact because they will lead to more efficacious regenerative medicine therapies for tendinopathy, as well as other protease- mediated degenerative conditions in a range of tissues throughout the body.

描述（由申请人提供）：肌腱病是一种常见的肌腱疾病，是由于工作场所重复运动或运动活动中可能导致严重疼痛和长期残疾而引起的。肌腱病的标志是破坏细胞外基质（ECM），尤其是胶原蛋白，这导致组织机械性能和功能的丧失。尽管各种类别的ECM蛋白酶与肌腱病的组织变性有关，但它们的相对量和表达的时间仍不清楚。缺乏知识严重阻碍了治疗的发展，从而为这些酶提供抑制剂，以减少病理的进展并改善肌腱病的愈合。 我们的长期目标是制定改进的再生医学策略，以帮助修复肌腱疗法组织。该提议的中心假设是，使用可持续递送蛋白酶抑制剂的可注射的生物材料对肌腱病的蛋白酶活性的长期调节将导致肌腱组织结构和机械性能更大，而没有载体的抑制剂。我们的总体目标将通过以下两个具体目的测试我们的中心假设来实现：1）研究与大鼠苏帕斯帕质肌腱过度使用模型中与ECM降解相关的蛋白酶和抑制剂。 2）评估蛋白酶抑制剂持续释放对大鼠上张肌腱过度使用损伤发展的影响。 拟议的工作具有创新性，因为它采用了良好的控制载体来实现局部持续释放蛋白酶抑制剂，以防止肌腱病中进一步的组织变性。预计这些研究的结果将产生重大影响，因为它们将导致肌腱病的更有效的再生医学疗法，以及整个身体一系列组织中其他蛋白酶介导的退化状况。