s100a4 Signaling in Fibrotic Diabetic Tendon Healing

纤维化糖尿病肌腱愈合中的 s100a4 信号转导

• 批准号: 10360571
• 负责人: Alayna Loiselle
• 金额: $ 33.54万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360571
• 关键词: Acute; Animals; Attenuated; Binding; Cells; Cicatrix; Clinical; Data; Diabetic mouse; Extracellular Matrix; FDA approved; Failure; Flexor; Impaired healing; Impairment; Incidence; Individual; Inferior; Injections; Injury; Knock-out; Knowledge; Mechanics; Mediating; Mus; Myofibroblast; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Outcome; Peptides; Pharmaceutical Preparations; Pharmacology; Population; Production; RAPGEF2 gene; Role; Rupture; S100 Calcium Binding Protein; S100A4 gene; Signal Transduction; Signaling Molecule; Site; Tendon Injuries; Tendon structure; Testing; Tissues; Trifluoperazine; Type 2 diabetic; Up-Regulation; antagonist; diabetic; diet-induced obesity; extracellular; healing; impaired driving performance; improved; injury and repair; macrophage; mechanical properties; mouse model; new therapeutic target; non-diabetic; prevent; receptor; receptor binding; receptor for advanced glycation endproducts; regenerative; repaired; response; restoration; small molecule; sound; therapeutic target; translational applications

Effective surgical repair of tendon injuries is limited due to a propensity for scar tissue mediated healing rather than regeneration of native tendon structure. This fibrotic scar tissue results in impaired tendon function due to extracellular matrix (ECM) disorganization and inferior mechanical properties, relative to healthy tendon. Type II Diabetes Mellitus (T2DM) dramatically exacerbates this healing paradigm resulting in a more profound loss of tendon function, and increased incidence of re-rupture. Our understanding of the mechanisms that govern increased fibrotic healing in diabetic tendon remains limited, and this gap in knowledge has resulted in a paucity of therapeutic targets to improve clinical outcomes. Our previous studies have utilized a murine model of diet-induced obesity and T2DM that results in increased scar-formation and inferior mechanical properties during tendon healing, however, the mechanisms driving these impairments in healing are unknown. Our preliminary data identify extracellular S100a4 (S100 calcium binding protein 4A) signaling as a key driver of fibrotic tendon healing in non-diabetic animals. S100a4-haploinsufficiency decreases scarring and accelerates improvements in mechanical properties, relative to WT, while S100a4-cell depletion also decreases scar tissue formation, but decreases mechanical properties, suggesting that S100a4-producing cells are required for mechanically sufficient tendon healing. Given that S100a4 and RAGE expression are dramatically increased in diabetic tendon repairs we propose that fibrotic healing occurs to a greater degree in diabetic tendons than non-diabetic due to elevated S100a4-RAGE signaling. Thus, in the present study we will use a murine model diet induced obesity and T2DM in conjunction with acute tendon injury and repair to test the central hypothesis that inhibition of the increased and sustained activation of pro-fibrotic S100a4-RAGE activity in diabetic tendons will promote mechanically superior, regenerative tendon healing. We will test this hypothesis through the following specific aims: Aim 1: Identify the S100a4-producing cell population during tendon healing and the specific effects of S100a4 conditional deletion on scar tissue formation and acquisition of mechanical strength after injury in diabetic tendons. Aim 2: Define the effects of global and macrophage-specific deletion of RAGE on scar-mediated diabetic tendon healing as a mechanism of reduced S100a4 signaling. Aim 3: Assess the efficacy of small molecule inhibition of S100a4 and RAGE to improve diabetic tendon healing.

有效的肌腱损伤手术修复受到限制 而不是天然肌腱结构的再生。这种纤维化疤痕组织会导致肌腱功能受损 相对于健康肌腱，细胞外基质（ECM）混乱和劣等机械性能。类型 II糖尿病（T2DM）极大地加剧了这种愈合范式，导致更深刻的损失 肌腱功能，并增加重新爆发的发生率。我们对管理机制的理解 糖尿病肌腱中纤维化愈合的增加仍然有限，知识的差距导致了 缺乏治疗靶标以改善临床结果。我们以前的研究利用了鼠模型 饮食诱导的肥胖和T2DM的疤痕形成增加和劣等的机械性能 然而，在肌腱愈合过程中，尚不清楚驱动这些损伤的机制。我们的 初步数据识别细胞外S100A4（S100钙结合蛋白4A）信号传导是 非糖尿病动物中的纤维化肌腱愈合。 S100A4-悬浮液减少疤痕和加速 相对于WT的机械性能的改善，而S100A4细胞耗竭也减少了疤痕组织 形成，但降低了机械性能，这表明需要S100A4产生的细胞 机械上足够的肌腱愈合。鉴于S100A4和愤怒表达在 糖尿病肌腱维修我们建议，糖尿病肌腱的纤维化愈合比 由于S100A4-RAGE信号升高而导致的非糖尿病。因此，在本研究中，我们将使用鼠模型 饮食诱导肥胖和T2DM与急性肌腱损伤和修复一起测试中心假设 抑制糖尿病中促纤维化S100A4-RAGE活性的增加和持续激活 肌腱将促进机械上优越的再生肌腱愈合。我们将通过 以下具体目的：目标1：确定肌腱愈合期间产生的S100A4产生细胞群 S100A4条件缺失对疤痕组织形成和机械强度的获取的特定影响 糖尿病肌腱受伤后。目标2：定义愤怒的全球和巨噬细胞特异性缺失的影响 在疤痕介导的糖尿病肌腱愈合中，作为降低S100A4信号传导的机制。目标3：评估 小分子抑制S100A4和愤怒的功效以改善糖尿病肌腱愈合。